Robert Williams - US grants

Amino acids are the building blocks of proteins, and thus they, and their chemistry, occupy an important position in biochemistry. Nature is able to efficiently make amino acids in a highly specific fashion because it employs enzymes. However, many amino acids of potential use are not synthesized by nature, and so the chemist is in need of tools to make these compounds with the same specificity as found in nature. This project in the Organic and Macromolecular Chemistry Program is developing such reactions for which the chemistry community will have great use. The overall objective of the proposed research is to develop efficient and practical methodology for the asymmetric synthesis of alpha-amino acids based on carbon-carbon bond constructions of electrophilic glycine-derived templates. In addition, the free radical and electrocyclic couplings to these glycine-templates will be investigated. On the practical side, access to either D- or L- configured amino acids in high optical purity and chemical purity will be the primary utility of this research. These selective coupling reactions will be achieved by a careful study of the fundamental chemistry of hemi-amino acetals as substrates for cationic and radical reactions with a variety of organometallic reagents. A new organotin acetylide coupling reaction has been discovered and will be investigated as a means for preparing vinyl and alkynyl alpha-amino acids which have potent biological activities. Several second-generation chiral auxilliaries will be investigated to broaden the scope of the electrophilic glycine template concept. The new methodology will be demonstrated with total syntheses of several representative, complex amino acids.

The major histocompatibility complex, H-2 in mouse and HLA in man, probably controls host resistance and immune response to malignancy through numerous mechanisms which we collectively term immune response gene phenomena. In a single widely studied model system called P815 the first six years of this project have demonstrated that two or more genes of H-2 can determine resistance to transplanted P815 in the histocompatible tumor resistance model which depends on the hybrid effect whereby P815 (DBA/2 origin) is relatively resisted by (C57BL/6 x DBA/2)F1 hybrids compared to DBA/2 mice. This B6D2F1 vs D2 difference involves the H-2Kb gene because replacing B6 with a variety of mutants at H-2k[unreadable]b[unreadable] can lead to effects ranging from complete loss of the hybrid effect (bm10) to development of super resistance (bm8). The I-A[unreadable]b[unreadable] gene is also involved because use of bm12 in place of B6 results in diminished resistance. The hybrid effect can be transferred to thymectomized, irradiated D2 mice with T-cell depleted hybrid bone marrow plus hybrid thymus epithelium. Different determinants are involved in the marrow stem cell and thymus because responder bm8 x D2 thymus epithelium alone fails, while bm8 x D2 stem cells require only that the thymus epithelium is hybrid type (i.e., bm10 x D2 epithelium works but D2 epithelium fails). No genes of the B6 H-2D end or non H-2 are involved. One or more non H-2 genes from C57BL/10 can be involved in the thymus epithelium effect but no non H-2 genes are required in intact animals by studies using RI lines. The objective of the project is to further investigate the immunological and genetic parameters involved in these phenomena. Since B6, bm8, and bm10 differ only by a few amino acids in the H-2K[unreadable]b[unreadable] molecule, these studies can add some precision to studies of tumor immunology. (SR)

The aims of the proposed research are to study the interaction of tubulin with specific, tight-binding ligands and apply the information obtained to elucidating the properties of tubulin. Tubulin is present in eucaryotic organisms and can exist in a polymeric form called microtubules. Microtubules have a role in several diverse cellular functions, e.g., mitosis, secretion, hormonal action, but in the presence of ligands such as colchicine these processes are disrupted. The ultimate goals of the proposed research are elucidation of the conformational changes occurring on ligand binding to tubulin and isolation of the suspected endogenous inhibitor/regulator of microtubule formation. Examination of the colchicine binding site through fluorescent and spin-labeled analogs will provide the necessary data to achieve these goals. Deacetylcolchicine (DAC) and [4-3H]-DAC allow the synthesis of a variety of ligands that show tight binding to tubulin. The fluorescent derivatives provide information on the microenvironment and binding characteristics of tubulin through fluorescence emission spectroscopy and polarization measurements. Equilibrium dialysis and an HPLC modification of the Hummel-Dreyer procedure to determine equilibrium binding parameters will give additional information on the nature of the CLC or analog binding to tubulin. The spin-labeled derivatives examine the binding site by EPR, circular dichroism (CD) and magnetic CD as well as probe conformational changes that may occur in tubulin. Knowledge of the binding site, preparation of a tubulin-affinity resin and preparation of a colchicine-affinity resin will allow purification of tubulin as well as isolation of the endogenous ligand. The ligand interactions between tubulin and colchicine analogs will provide fundamental information regarding tubulin structure. The research proposed involves techniques of synthetic, bioorganic, biophysical, and biochemical protein chemistry.

The scope and quality of undergraduate research in experimental psychology is being expanded and upgraded. The new equipment is allowing laboratory experimentation in four areas: psychomotor performance; biofeedback; operant conditioning; and perception and cognition. As a liberal arts university for deaf students one focus of laboratory experimentation and research in the undergraduate experimental psychology course is on the sensory, motor, cognitive and physiological concomitants of deafness. Under the plan students are learning the basic principles of experimental design, data analysis, and preparation of reports by conducting experiments which are both interesting and instructive, utilizing modern and advanced instrumentation. Psychomotor equipment, biofeedback equipment, and operant conditioning equipment have been added as well as a constant illumination projection tachistoscope. In addition to strengthening the undergraduate course in experimental psychology, the equipment is contributing to improvements in other experimentally-oriented courses, such as perception, learning, motivation and independent study (supervised student research).

The principal aim of this proposal is to provide a complete structural analysis of ganglion cell growth cones and their contactss with other fibers and glial cells in the optic pathway of the fetal primate. No such analysis of growth cones exists yet in any species. This work is an essential prerequisite if we are to identify an understand the morphological substrates and ultimately, the molecular interactions that guide the growth of optic axons. The explicit objectives are to: 1. Compare and contrast the form and fine structure of growth cones in the nasal and temporal halves of retina, in the optic nerve, chiasm, and trast, and in target nuclei at several stages of development. The analysis will be based on 3- deimensioanla reconstructions from serial sections. 2. Characterize and quantify the local and global distribution growth cones in the optic pathway and their contact relations with different classes of glial and neuronal processes from the time when growth cones first enter the optic stalk through to the end of axon ingrowth. 3. Experimentally test the hypothesis that interactions between growth cones in the optic chiasm or optic tract regulate the development of the unique pattern of partial decussation that characterizes the primate visual system. Anterograde and retrograde tracer transport methods will be used to label specific populations of ganglion cells, their axons, and their growth cones. In recent studies I have identified and characterized growth cones in the optic nerve of the cat and monkey at the ultrastructural level, and I have demonstrated that growth cones are remarkabley variable in form, ultrastructure, and position. In collaboration with my colleagues, I developed new analytic techniques that now make possible a far more comprehensive study of growth cones The quantitative in situ analysis of growth cone should answer several outstanding questions, among them: How do the shape and ultrastructure of growth cones change in response to their environment? Are there structural differences between growth cones that have different destinations? How are the earliest pioneers in the optic pathway different from growth cones that follow? Do growth cones express an affinity for glial surfaces or basal lamina, and if so, do these preferences change with age or position? What interactions are there between growth cones and pre-existing axons that may help explain global patterns of axonal growth? How stable are these interactions and relations? Although fundamental, these issues have not been studied in any detail in any species and have not been studied at all in primates. The results of this work should have a direct bearing on several important hypotheses concerning the growth of axons and should result in new insights into the development of the visual system that will be of theoretical and clinical importance.

This Department has initiated a series of courses with emphasis in Biotechnology. The new fermentation equipment purchased through this grant is making it possible to offer laboratory components of these courses. One 7.5-liter fermenter and two 2-liter fermenters are updating and supplementing existing equipment used in the Biotechnology- related courses, allowing introduction of current fermentation and chemical engineering techniques. This equipment also will be made available to students conducting undergraduate research. The new equipment helps students acquire hands-on experience with scientific equipment they may encounter as they go on to advanced studies or to employment in Microbiology-, Biology- or Chemistry-based careers.

This proposal is a continuing request to study cyclization reactions leading to the formation of medium and large rings (8-16 members) by the generation of a new carbon-carbon bond. The palladium catalyzed coupling reaction of an organic electrophile with an organotin group is an ideal reaction for this construction since it is a fast, high yield reaction that takes place stereospecifically under mild conditions and tolerates a wide variety of functional groups. Thus a prime objective of this research is the development of the intramolecular cyclization of a molecule containing an organic electrophile and a vinyltin unit at the termini. A knowledge of the phosphine type as well as the preferred solvent is critical to designing a catalyst supported on a highly cross-linked polymer, the purpose of which is to optimize the intramolecular reaction and reduce the intermolecular oligomerization. Thus, another goal is the rational design of a polymer supported catalyst. It is also the purpose of this research to determine which electrophilic types and organotin partners will participate in the coupling to give high yields of cyclized products. Broadening the scope of the cyclization reaction, particularly to the coupling reactions of vinyl electrophiles with organostannanes, will permit the synthesis of a wider variety of products. Finally, a key objective is the utilization of these cyclization procedures in the synthesis of a variety of biologically active ring compounds. In particular the ring systems of the polyoxo-macrolides produced by streptomyces microorganisms such as methynolide (12-membered), ingramycin (14-membered), erythronolides and mycinolides, tylonolides, or carbonolides (16-membered) as well as the ring systems of the beta-resorcyclic acid macrolide group such as zearalenone (14-membered) or milbemycin beta3 are potential targets. The synthesis of an important new class of antitumor antibiotics containing the conjugated enediyne chromaphore to which neocarzinostatin, calichemicin and esperamicins belong is especially attractive, since these molecules are highly functionalized yet are unstable, particularly in the presence of nucleophiles.

Twenty faculty members from two-year colleges in the Gulf Coast Consortium of Community Colleges will have an opportunity to update their knowledge and skills through participation in a four-week workshop. Areas of biology that will be emphasized are biochemistry, cell biology, microbiology, immunology, genetics, and physiology. These areas were identified as areas of great importance, through a needs assessment. They are areas which have been developing rapidly in recent years. After the four week course, follow-up seminars will occur during the school year at Baylor and the community colleges to establish continuing interactions and a formalized network between Baylor faculty and the two-year college faculty. The university has requested overhead at a reduced rate.

This award is being made by the Chemistry Division to enable the participation of 13 younger U.S. scientists in the Bilateral NSF- SERC Joint Workshop on Asymmetric Synthesis which will be held at the Pingree Park facility of Colorado State University, Pingree Park, Colorado, July 3-8, 1990. They will participate in the Workshop with 12 young scientists from Great Britain. The purposes of the workshop are (1) to expose them to the broader community of international scholarship, and (2) to build long-term bridges for productive international researh collaboration and knowledge exchange. Asymmetric synthesis has become an area of intensive research interest and significance in chemistry. The strict demands placed on the chemical and optical purity of new marketable drugs makes the discovery and implementation of new and efficient asymmetric chemical constructions a primary concern in chemistry.

The three principal investigators, together with junior faculty, postdocs, and graduate students, do research on a wide variety of problems in geometry, topology, and analysis. Some of the topics currently under investigation include symbolic dynamics, gauge theory, wave equations, topological quantum field theory, and index theory. Much of the work has direct ties to ideas in theoretical physics, specifically to dynamical systems and quantum field theory.

tissue mosaicism; developmental neurobiology; histogenesis; retina; cell growth regulation; cell type; species difference; autoradiography; genetically modified animals; laboratory mouse; in situ hybridization;

This award will support the participation of six U.S. scientists in a joint seminar on "Selectivity in Synthetic and Bio-organic Chemistry," to be held in Tokyo, Japan, June 2-7, 1991. The focus of the meetings will be on the dynamic scientific advances in the area of asymmetric synthesis, which spans the entire spectrum of organic and inorganic chemistry. A U.S.-Japan seminar on this subject in 1981 served as an opportunity for research groups in the two countries to share ideas and information. During the last decade, however, there has been a virtual explosion in the discovery of reactions that deliver levels of stereocontrol once thought to be impossible to achieve via non-enzymatic means. The impact of these new tools, coupled with the new enzymatic and microbial technologies, has dramatically redefined the way absolute stereochemical, regiochemical and functional group selectivity issues in synthesis are being addressed in both academic and industrial environments. A multitude of new chiral reagents and catalysts now exist that are capable of exerting near-perfect control over those bond constructions where new stereochemical relationships are established. The development of these new technologies are based on recent, deep understanding of fundamental issues of selectivity and molecular recognition. The enormous importance of this area is manifested in the highly international and cross-disciplinary nature of the primary contributions in the literature. The co-organizers of the seminar are Professor Robert M. Williams of Colorado State Unversity and Professor Kenji Koga of the University of Tokyo. The main topics to be discussed are new asymmetric synthetic methodologies; enzymatic, whole cell and cell-free bio-reactor technologies; total synthesis of natural products; biosynthesis; catalytic antibodies; and reaction mechanisms. In addition, a poster session will be organized for young Japanese industrial chemists.

9411994 Williams Nontraditional Manufacturing processes are being used to produce geometrically complex and highly accurate parts from modern materials. This project involves an effort to link abrasive flow machining (AFM) research with a leading machine tool builder of the equipment. The project will involve the principal investigator spending one summer at the machine tool builder. The project entails three major objectives: (1) Integration of abrasive flow machining research results into industrial applications. Particularly, the use of the acoustic emission monitoring system. (2) Involvement of graduate engineering students in the AFM research projects. This will include students from colleges and universities. (3) Exposure of the academic researcher to the competitive issues facing the machine tool builders. Expected benefits include enhanced technology of the abrasive flow-machining systems, greater understanding of AFM and better awareness of industry needs, and the establishment of long-term collaborative research efforts.

9453925 Benner This three year project will provide internship experiences for 300 teachers of grades 9-12 in the eleven counties and their school districts surrounding the Wright Laboratory. The teachers will be engaged in research over two summers and will have additional courses and other enhancement workshops to transfer new content and pedagogical knowledge to their classrooms. This will include 'real world' applications to discovery based approaches in their classrooms. The project will start with a smaller number of teachers in the summer of 1995 (57) ramping up to 93 in year two and 155 in year three or 1997. Application is limited to teachers in the Ohio West Region of the Ohio State Systemic Initiative. The cost share represents 56% of the funds requested from the Foundation.

DESCRIPTION: Neurons in the brains of different mammals are almost indistinguishable in structure and function, but their numbers vary by more than three orders of magnitude. This variation has part of its origins in a set of undefined genes that control rates of cell proliferation and cell death in different pools of neural precursor cells. Some genes must have global effects and control the scale of the entire CNS. Other genes must have specific effects on specific cell populations. collectively, these genes are not only at the root of brain evolution, but they are very likely to be key genes that control the normal development of the brain. Major technical advances now make it practical for the first time to map genes responsible for complex neuronal traits. These advances include (1) a quadrupling of the density of the genetic map, (2) the ease of genotyping marker loci distributed across the entire genome, (3) biometric methods to map quantitative trait loci (QTLs), and (4) novel magnetic resonance imaging methods that can generate precise quantitative data on many different parts of the brain. The project proposed by the applicant will use these new tools to map putative genes that contribute to the regulation of cell number in various CNS structures. The applicant proposes three specific ways to approach this problem. In the first, he will analyze two sets of recombinant-inbred mouse strains (BXD and BXH) to determine the number and location of genes controlling retinal ganglion cell number in mouse. This effort has already yielded a locus on chromosome 11 (Rcn-1) that is responsible for the majority of the genetic differences in the two parental strains. In year three the applicant proposes to repeat this analysis on brains from F2 intercross progeny of (CAST/Ei x BALB/cJ)F1s. Part of this first aim will be to do a developmental analysis of the highest and lowest strains in order to determine whether the differences arise from cell death or cell division. The second aim will be to expand this study to the target of the retinal ganglion cells, namely the lateral geniculate nucleus. Counts of both source and target neurons will be made in large numbers of animals and the variations will be correlated with each other as well as with segregating loci in two diverse strains, BALB/cJ and C57BL/Ks as well as F2 intercross progeny of (CAST/Ei x BALB/cJ)F1s as well as various BXD recombinant inbred lines. The third specific aim will be similar in approach but instead of using cell counts of neurons in the visual pathway, volumetric measurements will be taken using a customized MRI radio frequency coil to analyze fixed brain tissue. The analysis will be done on different RI lines as well as mice from the (CAST/Ei x BALB/cJ)F1 intercross.

The objective of this research is to develop balanced and integrated research and education goals related to the development of Abrasive Flow Machining (AFM). The research studies are to: (1) develop a process model for AFM utilizing wear mechanisms and characteristics about the viscoelastic carrier, (2) expand the acoustic emission monitoring to multiple passages and new materials, and (3) investigate the potential application of AFM for post-process finishing of stereolithography prototypes. On the education side, cooperative learning methodologies will be integrated into the curriculum for select manufacturing courses, and two new courses, Advanced Computer-Aided Process Planning and Environmentally Conscious Manufacturing, will be developed. Research and education program results will be formulated into Internet-based software testbeds and primers accessible to faculty, students and industry engineers. There exists a vital need for flexible finishing processes that are capable of handling intricate, precise geometries with a wide range of materials and in a variety of machining conditions. AFM has proven effective in fulfilling this need in a limited range of applications. A comprehensive research and education effort is essential to develop the necessary scientific knowledge and technology base of AFM to realize its full application potential.

The SIR provided [1_13C, 90%proline; . 15g [1_13C, 98%]tryp; .35g [U_13C, ?9]isoleucine;. 159g The paraherquamides are complex, heptacyclic, toxic mold metabolites, isolated from various Penicillium sp.The brevianamides A and B are structurally related natural products that display potent insecticidal activity. The brevianamides are also produced by Penicillium sp. molds. We are pursuing the identification of a new mechanistic class of enzymes that are involved in constructing the bicyclo [2.2.21 nucleus of the brevianamides/paraherquamides. We have obtained compelling experimental evidence that this unique ring system is very possible constructed via an enzyme-catalyzed intramolecular Diels-Alder cycloaddition reaction. Despite its widespread use in synthetic organic chemistry, the Diels-Alder cycloaddition reaction does not occur frequently in nature and there is not a single documented example of an enzyme that catalyzes this most ubiquitous synthetic ring-forming reaction. The Penicillium sp. that produces the brevianamides/paraherquamides may be a rare, but vitally important example of the existence of Diels-Alderases. One of the most significant objectives of this project is to characterize this rare catalyzed, biosynthetic construction. Using amino acids provided to us by the SIR, we have established that the 0-methyl proline ring in paraherquamide is derived from L-He and not via the SAM-methylation of L-proline. In addition , we have recently shown that L-tryptophan is the biosynthetic precursor to the dioxepin oxindole half of paraherquamide and that the N-methyl group is derived from L-Met. We have previously synthesized the tritiated piperazinedione and have demonstrated that this substance is efficiently incorporated into brevianamides A and B. Our current efforts are directed toward synthesizing the P-methyloproline derivatives containing 13C-labels for biosynthetic feeding experiments. We wish to establish the exact pathway by which the L-Ile is converted into P-methyloproline and thence, into paraherquamide A.

The focus of this research is the development of synthetic techniques for the preparation of alpha-amino acids. The main classes of methodology to be explored include: 1) allyl and crotyl silane/stannane additions to oxazinal-based oxonium ions to access hydroxymethylene peptide isostere; 2) an asymmetric (1,3) dipolar cycloaddition approach to spirotryprostatin; 3) unsymmetrically beta, beta-disubstituted alpha-amino acids via inter- and intramolecular SN2' reactions and via radical additions to E- and Z-alpha, beta-dehydro oxazinones; 4) preparation of Z-beta, gamma-unsaturated-alpha-amino acids and Z-1-aminocyclopropanecarboxylic acids. With this renewal award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Robert M. Williams of the Department of Chemistry at Colorado State University. Professor Williams will focus his work on developing efficient, selective and practical methodology for the construction of biologically important alpha-amino acids and their derivatives in optically pure form.

The Division of Mathematics has reflected the national trend toward integrating computing technology into its instruction, but to date that has been limited to hand-held graphing calculators. In order to implement further curricular changes our students must have access to desktop personal computers running mathematical software. This project implements a computer laboratory for classroom instruction and student use in differential equations and statistics. By adapting and implementing materials and practices from projects including the work on differential equations by Blanchard, Devaney, Coleman, Borelli and others and the work on statistics by Rossman, Schaeffer and others, these courses enhance instruction and broaden student activities to include work on computationally intensive real world problems. Although the initial focus is on two specific subject areas, we intend to extend the impact of the laboratory to other mathematics areas such as linear algebra and operations research.

The objective is to elucidate spectroscopically the mechanisms used by four different biochemical systems (ferrochelatase enzyme, catalytic DNA, catalytic RNA, and catalytic antibodies) for insertion of metal ions into porphyrins. Understanding these mechanisms should provide better insight into erythropoietic protoporphyria, a disease resulting from inactivation of ferrochelatase. Laser excitation within an electronic transition of a molecule gives rise to enhanced Raman scattering from selected vibrational modes. By comparing the resonance Raman spectra of solutions containing only porphyrin with solutions containing porphyrin bound to one of the four catalysts, structural distortions of the porphyrin induced by the catalyst may be identified. Subsequent analysis of the Raman scattering intensities using a combination of ground state vibrational force fields, structural calculations on the excited state, and resonance Raman transform theory will yield quantitative values for the local mode distortions induced by the catalysts. Different mutants and strains of the ferrochelatase enzyme will be prepared and studied to determine which amino acid residues are responsible for substrate distortion and to elucidate the nature of the Fe-S cluster found in mammalian strains of the enzyme. Catalytic antibodies with varying degrees of activity will be examined to determine if the extent of structural distortion can be directly correlated with activity.

DESCRIPTION (Adapted from applicant's abstract): We propose to refine and extend several efficient morphometric and physiological measurements from eyes and retinas of common inbred and recombinant inbred strain of mice. One emphasis of this work is to develop significantly faster ways to carry out unbiased and reliable quantitative analyses of murine retinas. To explore the genetic basis of eye disease, we are acquiring data from mice belonging to over 100 strains and crosses. Some of these strains have already proved to be valuable models for studing serious diseases that compromise human vision--glaucoma, myopia, diabetic retinopathy, and retinitis pigmentosa. We now are adapting efficient clinical diagnostic procedures (cryostat sectioning) and video-enhanced DIC microscopy to carry out a comprehensive biometric survey of the range of variation in eye, retinal, and optic nerve architecture. Data are acquired from mice of both sexes and a wide range of ages. Electroretinograms, pupillary reflexes, and optical measurement of eyes will also be obtained to assess functional aspects of vision in numerous and diverse strains. All of these data are being integrated into a sophisticated and universally accessible database available on the World Wide Web at nervenet.org.

SUBPROJECT ABSTRACT NOT AVAILABLE

DESCRIPTION (Adapted from applicant's abstract): Myopia is an extremely pervasive abnormality of vision that is usually caused by excessive growth of the posterior part of the eye relative to the optical power of the cornea and lens. The cumulative cost of myopia and its treatment is huge. The onset and progression of myopia are strongly influenced by environmental factors, but the risk of becoming myopic is clearly influenced by genes. The central aim of this work is to determine what genes and molecules normally regulate the growth of different parts of the mammalian eye and to then assess whether any of these same genes contribute to optical abnormality in humans. The first aim of this project is to systematically map genes that selectively influence the growth of the eye, the lens, the cornea, and the retina of mice. Using novel quantitative trait locus (QTL) interval mapping methods, more than 10 gene loci that selectively affect the growth of different parts of the eye will be mapped with F2 intercrosses. As part of the second aim, these QTLs will be mapped with far greater precision (a critical region of 1‑2 cM) using special mapping resources‑advanced intercrosses and reciprocal congenic lines. Complementary methods will then be used to evaluate the most promising candidate genes linked with particular QTLs. The third aim is a developmental study of the mekics of eye growth in several important strains, and in specially engineered congenic strains. This work will test ideas about how genes and environmental factors affect the optics of eye development. Understanding how different QTLs affect different parts of the eye will ultimately contribute to a far better understanding of molecular and developmental mechanisms associated with eye growth in humans.

Abstract

Award: DMS-0072675
Principal Investigator: Daniel S. Freed

The geometry group at the University of Texas proposes to carry
out a variety of research projects, most of which are related to
physics. Dan Freed's current research focuses on questions in
geometry and topology arising from string theory. These include
the construction of determinant line bundles on manifolds with
boundary and the understanding of anomalies of actions which
arise in quantizing lagrangian field theories. Karen Uhlenbeck's
current research involves the geometric theory of integrable
systems, as well as a non-linear Schroedinger equation arising in
macroscopic theories of a ferro-magnetic continuum. These two
researchers are starting a project aimed at understanding the
appearance of integrable systems in conformal field theories.
Bob Williams is applying his expertise on attractors to the
construction of tiling spaces. Constantin Teleman is pursuing
several projects in the cohomology of infinite dimensional Lie
Algebras. He and his coworkers are making progress on the
MacDonald conjectures, and are also giving geometric
interpretations in terms of the Hodge cohomology of flag
varieties of loop groups. He is also interested in homotopy
equivalences between holomorphic and continuous mapping
spaces. Postdoctoral members of the group are Nurit Krausz, who
is working on direct computations for quantum field theory in
Minkowski space, and Adrian Vajiac who uses equivariant
localization techniques to study topological quantum field
theories.

At this point in time, geometry is a rapidly developing area of
mathematics. While research in geometry, like most of pure
mathematics, consists of the construction and development of
abstract concepts, the origins and ultimate applications for
these constructions are invariably examples and applications in
more applied fields. The influence of theoretical physics on
geometry is strong. For example, large numbers of geometers are
currently working on questions related to quantum groups, mirror
symmetry and quantum cohomology. Our group attempts not to work
on problems which have already been identified by mathematicians
as central, but in contrast we look at current ideas in physics
of all sorts and then find, clarify, and work on the
mathematically interesting questions more directly. Dan Freed's
work on string theory connects the physics ideas of quantization
with the mathematical subject of algebraic topology. His joint
project with Karen Uhlenbeck on the appearance of integrable
systems in certain quantum field theories requires an
understanding of field theory, integrable systems, and the very
important and basic ideas of symmetry. Constantin Teleman's work
deeply involves fundamental ideas of symmetry, as well as delving
into the question of how closely very messy functions can be
approximated qualitatively by polynomial-like objects. Some of
the geometric ideas come from other branches of physics, such as
the ferro-magnetic equations studied by Uhlenbeck. The tiling
spaces of William's come from beautiful examples such as those
constructed by Roger Penrose. Our efforts bring new ideas and
techniques into mathematics, rather than concentrating on
projects which are already popular.

IBN-0003982
NIH/NSF Human Brain Project
PI: Robert W. Williams
Informatics Center for Mouse Neurogenetics


The purpose of this project is to develop and exploit a suite of image databases, motorized Internet microscopes, and software to study the genetic basis of structural variation of the mouse CNS. Resources are open to the research community through an integrated web interface at . The focus of this project is to provide collaborative research environments for mapping quantitative trait loci (QTLs). QTL analysis is a burgeoning field that tackles complex biological traits modulated by many genes. Four new resources and technologies will be developed: 1) the Mouse Brain Library, 2) the Internet Microscope System, 3) the NeuroCartographer Project, and 4) the Neurogenetics Tool Box. Achieving the aims of these four projects will catalyze a new era in the structural analysis of the adult mammalian nervous system and will lead to a large number of novel lines of research on the development and aging of the human brain.

This research is funded in part by the National Science Foundation through its participation in the Human Brain Project, which is a Federal interagency research initiative, mandated by Congress as part of the "Decade of the Brain".

This CCLI-EMD Proof-of-concept has as its primary goal the integration of haptics technology into required undergraduate engineering courses to improve learning and teaching in the engineering program at the Ohio University. Haptics indicates force and touch feedback to the human from a computer. Commercially available haptic interfaces can greatly augment education: " feeling is believing". Teaching and learning can be more compelling, fun, and engaging with better student retention via the integration of haptics technology. Specifically, we are developing haptics-augmented software activities and Internet-based tutorials, and integrating these tools into undergraduate engineering physics and statics/dynamics courses. The PI has delivered similar products in the K-12 arena, sponsored by NASA.

Though this proof-of-concept haptics technology development and evaluation is taking place at Ohio University, we have a nationwide focus with a goal of systematic changing the nation's undergraduate engineering programs via integrated haptics technology and curriculum. The College of Engineering personnel are performing the haptics technology, software, and tutorial development. The College of Education personnel are leading the integration of the resulting technology into the undergraduate engineering curriculum, the transfer of project results to K-12 science and technology teacher preparation, and the project evaluation efforts at Ohio University.

The deliverables for this project include prototype haptics-augmented PC software learning activities, HTML-based tutorials, and integrated curriculum for physics and statics/dynamics courses. Pilot tests on each of these courses will be conducted to evaluate project results. The dissemination of the results of this project will consist of conference papers and a journal article. Also, we will study the potential of commercially disseminating the products of the project nationwide. We will submit a full development proposal to NSF CCLI-EMD at the project conclusion.

Keywords: Haptics, haptics-augmented software, haptics technology

DESCRIPTION (provided by applicant): Numerous non-genetic variables interact with gene variants to influence alcohol use, dependence, and relapse. One key influence is a complex mix of stressors. In common with other components of this INIA application, this project explores genetic, molecular, and cellular substrates of alcohol consumption in response to stress. Our focus is on using new high-resolution gene mapping resources and methods to dissect genetic interactions between alcohol, stress, and forebrain-midbrain anatomy. We use well characterized behavioral paradigm that are combined for the first time with sophisticated stereology and immunohistochemical analysis of the amygdala and key neuromodulatory inputs to the forebrain. Data from the molecular and structural analyses will be combined with EtOH-stress interaction measures to define shared and unique genetic determinants. The first aim is to systematically apply new quantitative trait locus (QTL) mapping methods to fine map alcohol and stress-related genes in mice. More than ten loci are being mapped and remapped with high precision (a critical region of 1-2 cM) using a set of -100 new types of recombinant inbred (RI) strains, an novel RI intercross (RIX) method, and interval-specific congenic lines. In parallel with these genetic studies, we will explore genetic and epigenetic interactions and codeterrninants of stress and alcohol consumption. We intend to systematically map genes that influence the number and distribution of three major neurotransmitter systems that modulate basal forebrain physiology serotoninergic cells in the dorsal raphe, noradrenergic neurons in the locus coeruleus, and dopaminergic cells in the midbrain. This aim links our analysis closely to the other transmitter-related components of the INIA. We will use unbiased stereological methods. We anticipate that the synergy between the structural and functional analysis will allow us to far more efficiently generate candidate genes that influence the development of alcoholism in humans.

[unreadable] DESCRIPTION (provided by applicant): One of the challenges facing primary care clinicians who recognize the important role that complementary and alternative medicine (CAM) has in their patients' lives is to understand how to effectively serve their patients' interests through integrating the CAM and allopathic care. Primary care clinicians need to better understand the patterns of CAM use by their patients in order to integrate that care into their services. This is especially important in communities where traditional medicine concepts continue to have an important role. RIOS Net is a primary care practice-based research network, whose 170 members are primary care clinicians serving New Mexico's Hispanic and American Indian communities. Through their practice experience, these clinicians have set a priority on research to identify effective ways to integrate their patients' allopathic and CAM care. [unreadable] [unreadable] This project will provide key building blocks toward a clinical trial assessing the outcomes of a model of integration of allopathic primary care with CAM in the Southwest's Hispanic and American Indian communities. The specific aims for this pilot project are to: 1) document the decision-making process behind the use of CAM modalities, allopathic care, and their integration by Hispanic and American Indian patients of primary care providers in the Southwest; 2) to identify barriers to integration and to communication about CAM between primary care providers, patients, and CAM providers; and 3) to develop a model of integrative care for Hispanic and American Indian primary care patients in the Southwestern US. A two phase study is planned, using qualitative interviews with Hispanic and American Indian primary care patients of members of RIOS Net, and using interviews and focus groups with primary care clinicians serving these patients. The results will be used to design subsequent studies assessing frequency of use of CAM in primary care patients and exploring CAM providers perspectives on the process of integration of care, and to construct the clinical trial of integration of allopathic and primary care. [unreadable] [unreadable]

The Robert Noyce Scholars Program at Indiana State University (ISU) is increasing the number and retention rate of licensed secondary school teachers in science and mathematics in high-need schools in the Indianapolis Public School system. Noyce Scholars are recruited from among transfer students entering ISU from two-year institutions, as well as from transitioning professionals with backgrounds in science and mathematics. Undergraduates receive scholarships to support their teacher training, and graduate students, entering ISU's Transition to Teaching program, receive stipends to offset the costs of attendance at ISU. Twenty-six future teachers are being trained and mentored in a well-established teacher education program, which builds on a long-standing partnership between ISU and the Professional Development Schools in the Indianapolis area. Students in the program take coursework that integrates both Indiana Academic Standards into content area training, as well as a problem-based learning approach to teaching science and mathematics. Noyce Scholars commit to teaching in the Indianapolis Public Schools for two years for each year of the scholarship. The intellectual merit of the project includes an evaluation of the effect of targeted teacher training for the urban environment as a strategy for transforming the urban setting into a learning tool for both students and teachers in training. ISU is also using its Noyce program to assess the value of problem-based learning in urban settings. The broader impacts include more and better STEM teachers and improved learning outcomes in an urban school district.

DESCRIPTION (provided by applicant): Environmental factors interact with gene variants to influence patterns of alcohol use, abuse, adaptation, addiction, withdrawal, and relapse. Ethanol is a highly soluble small molecule that has subtle allosteric effects on many molecular processes in the CNS and not all of its many targets are known. Individual differences in how humans respond to ethanol are also not well understood. This project leverages the broad expertise of INIA to explore and test genetic, molecular, synaptic, cellular, and behavioral causes of alcohol consumption and the increased vulnerability following stressors. Our focus is on exploiting new high-resolution genomic resources (sequence data, SNPs, mRNA microarrays) to model networks of molecular and synaptic interactions in forebrain regions that have important roles in alcoholism. To ensure robust results we use two large genetic reference populations of rodents (BXD mice and HXB rats) and apply sophisticated statistical methods to generate hypotheses that are then subjected to rigorous experimental testing. We combine data from our own work with data from numerous other published studies using a systems genetics approach. This combined approach is made possible by our use of well studied genetic reference populations. We will define shared and unique genetic and synaptic factors that modulate ethanol use and the convergent effects of stress on ethanol addiction and relapse. In Aim 1 (Data Generation) we generate normative expression data and networks for four key forebrain regions (medial prefrontal cortex, nucleus accumbens, bed nucleus of the stria terminalis, and the basolateral amygdala) from complementary genetic reference populations with different genetic structures (inbred Rl and hybrid RIX lines). We are acquiring gene expression data for 48 brain regions in C57BU6J and DBA/2J lines. Our goal is to extract robust networks that are cross-validated and that have strong prospects of generalizing to admixed human populations. Data will be made publicly available on the GeneNetwork (GN) site (www.genenetwork.org). In Aim 2 (Model Construction) we develop open source programs and standard operating procedures to produce well defined and testable hypotheses. The INIA Models Work Group will be responsible for developing, testing, and using the INIA GeneNetwork (GN) and this software to construct explicit process diagrams and statistical models. We will integrate these models into GN for use and critique by INIA and NIAAA researchers. In Aim 3 (Predictive Validation), members of INIA will experimentally manipulate sets of isogenic lines (BXD and RIX), predicting whether they will be high or low responders using INIA standard operating protocols. The synergy among genetic, transcriptome, electrophysiological, and experimental studies and data sets will allow us to test the role of complex interactions in the mesocorticolimbic system that contribute to alcoholism and maladaptive stress response.

The objectives of this project are to develop and apply statistical methods for the analysis of data collected across multiple phenotypic domains from collaborative cross (CC) strains and their derivatives. These include a diallel cross among the eight founder strains of the CC and a recombinant inbred intercross (RIX) population consisting of the F1 progeny of CC strains. The use of genetically reproducible but outbred RIX animals will enable the integration of data across multiple phenotypic domains in animals with natural levels of heterozygosity. Analysis of this novel cross design will require new methodology development. We will implement analysis tools in the general statistical software package R. Performanceof new methodology will be assessed and validated using simulations and in applications to the experimental data. Integrated analysis of genetic, environmental and physiological variables will provide new insights into the role of stressors on whole organism biology. Specific Aim 1: We will develop and apply statistical methods for genetic mapping analysis of the collaborative cross recombinant inbred strains and their derivatives. The objective of these analyses will be to identify genetic factors that interact with experimentally defined stressors in their effects on mean and covariance of measuredphenotypes. Specific Aim 2: We will develop and apply statistical methods to conduct an integrated analysis of collaborative cross data across multiple phenotypic domains. We will focus on the application of graphical models that capture interactions among these phenotypes using intuitive visual representations.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Acanthosis Nigricans [AN] is a skin condition thought to be associated with diabetes and diabetes risk factors. AN has been found to be associated with people who are overweight. Most research has found that AN is associated with insulin resistance. However, other studies have not found AN to be an indication for insulin resistance, but rather a predictor of being significantly overweight. The purpose of the study is to look at patients who are of the same ethnicity, age, and weight range, and who have Acanthosis Nigricans [AN] to determine if they are more likely to have diabetes or risk factors for diabetes than patients who do not have AN.

DESCRIPTION (provided by applicant): The primary focus of this application is to study the total synthesis and biosynthesis of complex, biomedically significant natural products constituted of tetrahydroisoquinolines. The synthetic chemistry that will be developed shall be utilized to prepare analogues of the natural substances as biological, biosynthetic and mechanistic probes. This proposal is primarily hypothesis-driven, and extensively employs new synthetic methodologies developed in this laboratory for the construction of such agents. The specific aims of this program are to study the interaction of the natural antitumor antibiotics and mechanistically inspired synthetic analogs, including ecteinascidin 743 (Et-743), saframycin, jorumycin, tetrazomine, lemonomycin and the bioxalomycins with cellular nucleic acids. The DNA-alkylating capacity of these drugs compared with their ability to cause oxidative damage to nucleic acids will be explored. The synthesis of members of this class of antitumor drugs will continue to be developed with the objective of harnessing the synthetic methodology developed to make new, less toxic, more selective and more potent antitumor drugs. In addition, the tools of synthesis will be exploited to synthesize mechanistic probes for the interaction of these substances with cellular nucleic acids and proteins that bind to cellular nucleic acids. We have recently discovered that bioxalomycin 12 specifically cross-links duplex DNA at 54dCpG34 steps. We propose to elucidate the exact molecular structure of the covalent adduct. This finding has inspired new design concepts for simpler analogs based on the tetrahydroisoquinoline core that may be capable of alkylating and cross-linking DNA as well as potentially cross-linking DNA to DNA-binding proteins. The antiproliferative activity of this family of alkaloids is intimately associated with the capacity of these agents to bind to and covalently modify DNA. This is particularly evident in the case of Et-743. Plans are presented to mechanistically separate the DNA alkylation and cross-linking chemistry of these agents from their capacity to inflict oxidative damage on cells. The investigation of the biosynthesis of Et-743 with a particular focus on the late-stage assembly of the macrocyclic sulfide-bridged spiro-tetrahydroisoquinoline ring system will be pursued. We plan to apply high throughput genome sequencing methods using 454 technology to identify the Et-743 biosynthetic gene cluster from Ecteinascidia turbinata. The ultimate goals of the biosynthesis studies are to genetically engineer a fermentable microorganism to produce Et-743 for clinical use. PUBLIC HEALTH RELEVANCE: The purpose of this application is to utilize the tools of chemical synthesis to study the molecular details of how Nature biosynthesizes anti-cancer drugs. In particular, this program will deploy new technologies to produce the clinically relevant anticancer drug ecteinascidin 743 (Et-743) on industrially practical scale through genetic engineering of a microbial host. In addition, the chemical technologies being developed will be applied to the design and synthesis of new anti-cancer drugs.

The Administrative Core of the NM CARES HD will provide a range of support activities for the Center and its component cores, research projects, and individual investigators. A set of aims and subaims for the Core will focus on: providing leadership for the NM CARES HD;linking to collaborating institutional programs;systematically evaluating processes and outcomes of the NM CARES HD;providing research support and integration with research resources;an in-kind supported pilot project program and an in-kind supported national conference on disparities research;strengthening communication processes with key stakeholders; supporting community-based participatory research;and coordinating NM CARES HD functions. The Core will be led by Robert Williams, MD, MPH, the PI of the NM CARES HD, with Nina Wallerstein, DrPH, and Dennie Jones, MD, as Associate Directors. Key functions housed in the Administrative Core will be management and operations, information systems, and communications. Activities of the Core will be based on and support the conceptual model of disparities in indigenous Native American and Hispanic communities that is the foundation of NM CARES HD activities. A Community and Scientific Advisory Council composed equally of UNM and community leaders and stakeholders will meet twice yearly to review NM CARES HD operations and projects. Two leading researchers on health disparities will also consult with the NM CARES HD team on an annual basis.

Though much evidence exists of health disparities within minority and other marginalized populations, the real challenge lies ahead[unreadable]to develop, implement, and sustain effective strategies to eliminate health and social disparities within these diverse populations, and within often resource-poor settings. Community engaged research represents a transformative research approach to create necessary bridges between academics and communities (providers, other health care professionals, policy makers and community members and organizations) to translate science into multilevel practices that influence individual health behaviors, organizations and practice systems, community and cultural norms, policies, and, ultimately, improved population health equity and health status. This Community Engagement Core (CEC) therefore aims to build partnerships dedicated to research on health disparities, between UNM investigators and community residents in Native American and Hispanic communities suffering disparities. The specific aims are to: 1) create multi-directional authentic partnerships between academic researchers and community constituencies (clinicians/providers, policy makers and community members and organizations) to mutually identify a continually evolving disparities research agenda based on the priorities of Native and Hispanic communities in New Mexico;2) promote UNM researcher reflection and organizational assessment of barriers and facilitators to community engagement and to develop action strategies and best practices for enhancing community trust and university-community partnerships;3) develop co-learning and mentoring opportunities through a cohort of "intercultural health disparity scholars" and summer co-learning institutes aimed at: facilitating cross-cultural dialogue, understanding of CBPR methodologies, and capacity-building to bridge indigenous cultural knowledge and practices with empirically supported theories and interventions;and 4) translate and co-disseminate findings with our community partners to enact practice, program, and policy interventions in order to reduce health disparities and improve health equity. The CEC specific aims are built on a commitment to community based participatory research, intercultural and decolonizing research methodologies that embrace indigenous world views and rebuild community trust in research;and on supporting translational interventions that address the multi-level risk and protective factors of the Center conceptual model using empirically-effective and culturally-centered strategies to reduce disparities.

The goal of the project, which builds on prior NSF support, is to develop haptics-augmented software activities and Internet-based tutorials and to integrat these tools into undergraduate statics and dynamics engineering courses. Specifically the investigators are (1) developing a full suite of haptics-augmented statics and dynamics activities to complement standard textbooks; (2) evaluating these products in two large engineering schools; (3) developing curricula that integrates these products into statics and dynamics courses; (4) applying educational pedagogy research for experiential inquiry-based learning and implementing a learner-based hypothesis generation and testing procedure to encourage learners to translate tactile responses to their real world causes; and (5) using a design research approach in the evaluation process to make it an integral part of the development process. They are working to commercialize a unique CD-based set of software activities and tutorials that will enable students to change parameters, predict answers, interact with animations, and feel the results through the haptic device. The evaluation effort, under the direction of an experienced, independent evaluator, is examining student work captured on video along with student surveys and focus groups to monitor student learning. The broader impacts will include the dissemination of their products and results, particularly through commercialization and linking the material to successful textbooks.

DESCRIPTION (provided by applicant): The primary focus of this application is to develop more potent and less toxic, isoform-selective histone deacetylase (HDAC) inhibitors (HDACi) for use as anti-myeloma and anti-cancer drug candidates, biological tools for investigation of specific functions of individual HDACs and extension of this chemical class beyond antineoplastic indications. Specifically, we plan to optimize the structures of macrocyclic peptide analogues of largazole, and related naturally occurring HDAC inhibitors for HDAC class- selectivity by altering the amino acid sequence and zinc-binding functionality in accord with parameters derived from crystal structures of the target enzymes deploying additional computational and empiric insights. Analogues will be assayed for inhibitory activity against HDACs 1-11 in the laboratories of co- investigator Dr. James E. Bradner at the Broad Institute of Harvard-MIT and the Dana-Farber Cancer Institute and Dr. James R. Berenson at the Institute for Myeloma and Bone Cancer Research. Assessment of the safety and pharmacodynamic effect will be performed by Prof. Douglas Thamm and co- workers at the CSU College of Veterinary Medicine and Biomedical Sciences. Insight from the results of these assays will guide further alterations of the candidate structures. A computational co-investigator, Prof. Olaf Wiest, at the University of Notre Dame, will deploy homology model-based docking studies to further guide the design and optimization of new synthetic HDACi's. We have developed scaleable solution-phase syntheses of the known, highly potent natural HDACi's largazole and FK228 as well as the corresponding peptide isosteres and numerous synthetic analogs of these potent and naturally occurring HDACi's. Structural diversity within the analogs will be explored by varying three parameters: (a) amino acid sequence and constitution;(b) macrocycle size;and (c) zinc-binding arms. Particularly potent and/or isoform-selective macrocyclic peptide inhibitors that are produced by this approach will be targeted for re-synthesis as the corresponding depsipeptide congeners and profiled for potency and specificity in biochemical and cellular assays. Select isoform-specific analogs will be evaluated for in vivo tolerability and antineoplastic activity. PUBLIC HEALTH RELEVANCE: The purpose of this application is to develop new classes of drugs that target a new and exciting biochemical target recently recognized as being essential to the cancer cell cycle. The new target is a class of enzymes that exist inside all cells called histone deacetylase enzymes (HDAC's). Our multidisciplinary project brings together synthetic organic chemistry, computational modeling, chemical biology and clinical evaluation of potential inhibitors of HDAC's.

DESCRIPTION (provided by applicant): The University of New Mexico (UNM) proposes an innovative Center of Excellence titled the New Mexico Center for Advancement of Research, Engagement &Science on Health Disparities, or NM CARES HD. Based on an understanding of the common causes of health disparities across indigenous communities, NM CARES HD will apply a conceptual model that stresses three principles in interventions to eliminate those disparities: 1) community partnering, through community-based participatory research;2) multifactoral, multilevel interventions within a cultural and social context;and, 3) translating evidence-based and community-based practice. NM CARES HD will build on the foundations of a strong set of established, collaborating institutional programs, nationally recognized expertise in several key areas, long-standing productive partnerships with Native American and Hispanic communities, and a diverse interdisciplinary collaboration to achieve its overall goal. That goal is to create a vigorous, self-sustaining, research center that advances the scientific base of knowledge about interventions and solutions to health disparities in Southwestern Native American and Hispanic communities. A strong team of investigators with senior, NIH- funded leadership has come together to meet the NM CARES HD specific aims. An Administrative Core, a Research Core, a Research Training and Education Core, and a Community Engagement Core together with two research projects will be the initial composition of the NMCOE it works toward meeting a set of specific aims and subaims. Those aims are to: 1. Establish a multidisciplinary research center that advances the science of interventions to eliminate health disparities among Southwestern Native American and Hispanic communities;2. Enhance the ability of UNM researchers to compete for NIH individual, disparity- related research grants;3. Build a partnership, dedicated to research on health disparities, between UNM investigators and community residents in Native American and Hispanic communities. In meeting these aims, NM CARES HD will develop innovative structures and resources to support the expansion of research on interventions to eliminate disparities in these communities. The combined resources and institutional commitments of new faculty, and pilot project and national conference support make success highly likely. RELEVANCE (See instructions):

Behavioral health disparities among American Indian and Alaska Native youth are dramatic, particularly in terms of depression, suicide and post-traumatic stress disorder. The goal of this proposed community based participatory research (CBPR) project is to develop and pilot test elements of a public health prevention intervention model that is tailored to be culturally and socially appropriate for adolescents on the Mescalero Apache Tribal Reservation in New Mexico. We propose to partner with a Mescalero Mental Health Prevention and Intervention Task Force to (1) identify what serious MEB problems most need to be addressed (including, provisionally, depression, suicide risk, post-traumatic stress disorder, early symptoms of psychosis and coexisting substance abuse problems;(2) broaden the focus of existing Mescalero prevention programs to focus on a larger array of serious MEB's;(3) review and adapt screening scales for depression, suicide risk, PTSD, and early symptoms of psychosis to insure their cultural and social appropriateness for youth on the Mescalero reservation;(4) similarly review and adapt measures of symptoms resulting from contemporary and historical trauma and of desirable life function outcomes;(5) review and adapt a multifamily group (MFG) prevention treatment model to ensure its cultural and social appropriateness for youth on the Mescalero reservation;(6) conduct a one-year pilot of the feasibility of the resulting public health model (outreach, identification, referral, screening and intervention) in the Mescalero Apache School Based Health Center (SBHC);and (6) conduct a three year evaluation of the model including;a process evaluation of its ability to reach, enroll and treat the target population, obtain acceptability in the community, maintain fidelity over time to the program model, its potential for sustainability and export;and, most importantly examine outcomes in terms of student satisfaction with treatment, MEB symptom levels, quality of life impairment and clinical assessment of improvement to develop some sense of the model's potential for reducing disparities in behavioral health.

Background: Significant health disparities exist for Hispanics and Native Americans in screening and treatment for problem alcohol and opioid use in New Mexico. Despite the availability of methods for screening and brief intervention in primary care for problem alcohol use and opioid dependence, data continue to show that such strategies are underutilized. Improved alcohol and opioid services delivery in primary care will require innovative understandings of the community and primary care context in which these services are provided. Objectives and aims: The specific aims of this ecological, mixed method project are: 1) To more fully describe the complex factors influencing implementation of evidence-based screening and treatment for problem alcohol use and opioid dependence by conducting a three-phase mixed-method study in a primary care practice-based research network; 2) To more fully understand community level factors and perceptions of alcohol use, opioid dependence and the acceptance of screening and treatment for these problems in primary care;3) Based upon Community and Primary Care Provider feedback, create flexible models for matching approaches to alcohol and opioid screening and intervention with different primary care and community settings;and 4) To assess the feasibility of these models in enhancing screening and intervention for problem alcohol and opioid use in primary care. Design and methods: A multi-method, three phase study is planned, using survey, qualitative case study, interview, and observational data to conduct up to 12 primary care clinic assessments from which a pilot intervention study will be developed and implemented. The study will be conducted in a primary care practice-based research network and will use a participatory approach to engage community behavioral health and substance use partners. Outcomes: This study will produce data that will be used to create and test the feasibility of new model(s) for intervening in primary care clinics to enhance alcohol abuse and opioid dependence services. In contrast to previous ideas about changing primary care clinic to increase attention to problem alcohol use and opioid dependency issues, these innovative models will incorporate the situational and complex nature of primary care. Subsequent research will aim to test the effectiveness of interventions based on the new model(s) on a broader scale aimed at reducing substance use disparities among Hispanics and Native Americans.

The overall goal of the New Mexico Center for Advancement of Research, Engagement &Science on Health Disparities (NM CARES HD) is to create a vigorous, self-sustaining center of excellence that advances the scientific base of knowledge devoted to decreasing health disparities in Southwestern Native American and Hispanics communities. The Specific Aims of the NM CARES HD Reseach Core (RC) are to: 1. Provide research infrastructure and technical support to assure successful completion of current projects and facilitate development of new projects and researchers invested in health disparities research, with particular emphasis on supporting minority investigators; 2. Develop and facilitate research clusters to better inform and develop new projects, researchers, and methods aimed at reducing health disparities. Initial clusters will focus on community-based participatory research (CBPR) and decolonizing methods;race, ethnicity and health equity;mixed and novel methodologies;and translation to policy and practice; 3. Evaluate the activities within the Research Core and the program as a whole using various data sources, including interviews of community members and researchers who attend various presentations, participate in discussions regarding center topics, and are involved in proposed and future research projects. Two initial research projects will be supported. The RC will develop resources that all center disparity investigators can use, including a resource library;direct consultation with the RC faculty;funding for direct consultation from external experts in the field;other training opportunities. The following think tank study groups, "research clusters", will be formed to provide a forum for the exchange of ideas, expansion of knowledge, and development of new, innovative health disparity studies: CBPR evaluation science, disparity causation, integration of mixed research methods, and translating disparity research into primary care practices and policy. A comprehensive evaluation strategy for the center has been developed.

Project Summary/Abstract: Many studies have shown that racial and ethnic minorities do not receive therapeutic medical procedures at the same rates as non-Hispanic whites, with the strongest evidence of these racial disparities in the utilization of invasive cardiac procedures. The causes of these racial disparities remain unclear, but geographic and financial access, underlying morbidity, insurance status, and income cannot fully explain the differences. There is suggestive evidence that a contributing factor is a difference in the rate at which physicians offer these procedures to patients based on race and/or gender, and that such biases may be present in medical students. This innovative, multidisciplinary, multimethod study will investigate the prevalence and determinants of racial and gender biases in medical decision-making under conditions of scientific uncertainty of senior medical students. It will further develop information about the dynamics by which non-clinical factors become part of student medical decision-making, and the training environment in which this takes place. In doing so, the study will provide essential guidance to medical educators and developers of cultural competency training who aim to reduce the impact of this social determinant of health and accompanying racial and gender disparities in health service delivery. A nationwide mail survey of senior allopathic medical students will first be conducted to determine the prevalence of such biases using a set of clinical vignettes in which the race and gender of the patient will vary among the sample. The influence of patient race, gender and socioeconomic status on the rates of procedural recommendation by the students will be analyzed. Ecological case studies will then be conducted at each of 14 purposively selected medical schools to explore the context and dynamics of formation of student medical decision-making. Schools for the case studies will be selected based on summaries of response patterns to the survey, with sampling of schools for study that demonstrate greater or lesser degrees of influence of race and gender on their students' responses. In-depth interviews of students, faculty and staff key informant interviews, examination of cultural competency and student curricula and of admission processes are some of the data collection processes that will be used to explore the context in which student decision-making processes are formed, reinforced, or reduced. The findings of the combined survey and case studies will be used to prepare reports for schools, policy makers, and peer-reviewed scientific presentations and publications. The specific objective of this study is to develop and disseminate evidence-based recommendations for medical educators and developers of cultural competency training interested in reducing the role that such biases play in racial and gender disparities in health services delivery.

With combined biochemical, mutational, and protein structural analyses (eg. X-ray crystallography and Small angle X-ray scattering), we dissect functionally critical protein conformations, protein-protein and protein-nucleic acid interfaces. We are currently focused on examining structure/function of DNA end processing factor Aprataxin (APTX). APTX is a conserved eukaryotic DNA repair enzyme that is important for protection of cells from oxidative DNA damage, and APTX mutations cause the recessive hereditary neurodegenerative disorder Ataxia with Oculomotor Apraxia 1 (AOA1). In the ultimate step of DNA replication and repair processes, DNA ligases seal DNA nicks through an imperfect mechanism that can abort when the ligase encounters DNA termini harboring the products of oxidative or DNA-alkylation damage. Such "abortive ligation" generates a secondary form of damage, 5'-adenylated DNA-termini, which are corrected by APTX to protect genomic integrity. However, due to a lack of protein structural information, the molecular basis for APTX catalytic reversal of 5'adenylation damage, and how APTX is inactivated in the neurodegenerative disorder Ataxia with Oculomotor Apraxia 1 (AOA1) remain largely unknown. Towards understanding APTX mechanism we have developed robust overexpression systems for human and yeast aprataxin homologs and we aim to define molecular determinants of APTX DNA repair, and how APTX integrates into damage repair pathways through interactions with DNA break repair pathways through binding Xrcc1 (DNA single strand break repair, SSBR) and Xrcc4 (DNA double strand break repair, DSBR). We are specifically testing hypotheses that: 1) APTX Histidine triad (HIT) and Zinc finger (Znf) domains form a composite fused catalytic domain for DNA structure specific nick-binding, 5'-AMP recognition, and DNA-deadenylation processing, 2) AOA1 patient mutations disrupt APTX protein folding and/or directly impair APTX catalytic activities through active site distortion, and 3) The FHA domain and FHA-HIT linker provides a flexible leash targeting APTX DNA deadenylation activity to Caesin kinase 2 (CK2) phosphorylated XRCC4 and XRCC1 DNA repair scaffolds. Ionizing radiation (IR) and non-ionizing radiation from exogenous natural sources such as cosmic rays, radioactive elements in the environment, or from artificial sources including diagnostic X-rays mount a constant assault our genomes. Oxidative DNA damage from reactive oxygen species generated as by-products of mitochondrial respiration, during chronic inflammation, or upon exposure to environmental agents poses a threat to all cell types. Thus our knowledge of the DNA SSBR and DSBR repair mechanisms we are studying has critical implications for environmental health. Significantly, DNA repair defects underpin many human diseases associated with disorders of the nervous system and we are working to understand how heritable DNA repair defects impair damage surveillance and contribute to neurodegeneration.

The overall goal of the NM CARES HD Research Education/Training (RETC) is to enhance an already existing pipeline for interdisciplinary education for the purpose of developing a strong cadre of Individuals prepared to work collaboratively with peers and the community to conduct research on health disparities with underserved populations. The specific alms of the RETC are to : 1) Collaborate with the UNM Health Sciences Center's, Research Education, Training and Career Development component of the Clinical and Translational Science Center (CTSC) to enhance an existing training and education pipeline with model health disparities training and education resources to develop health disparities research awareness, interest and skills. The RETC will accomplish this by providing training materials, curricula and expertise (trained experts) for new and existing training programs in a variety of settings, using novel competency-and problem-based approaches;2) Increase mutual understanding between faculty and community researchers about the process of health disparities research by developing and implementing faculty and community researcher mentorship models. The faculty/community researcher mentorship models will allow junior faculty members to form a triad with senior faculty members with health disparities research expertise and community members who are willing to become leaders for the academic research within their communities. The education and training component will provide support to establish and enhance mutual respect and training opportunities so that academic and community members can partner to Implement research In communities experiencing health disparities and 3) Develop a NM CARES HD Health Disparities Conference that will Increase the bidirectionality and mutual understanding between faculty and community researchers around the process, training, challenges and successes of community based participatory research (CBPR) and health disparities research, and that will expose UNM researchers to emerging disparities research nationally. The Health Disparities Conference will serve multiple purposes: a) to highlight community and university activities around health disparities education/research b) to develop a state-wide community of researchers (community and university) who can collaborate on future health disparities research c) to serve as a recruiting tool for participation In NM CARES HD activities, d) to serve a public relations function by promoting the work of NM CARES HD and Its contributions to health disparities research activities, and e) to present innovative and emerging national disparities research to UNM disparities researchers.

DESCRIPTION (provided by applicant): Though much evidence exists of persistent environmental health disparities within minority and other marginalized populations, the real challenge lies ahead-to develop, implement, and sustain effective intervention strategies to reduce health disparities in these diverse populations, be they policy, clinical, social, or behaviorally based. Researchers at the University of New Mexico Health Sciences Center (UNM HSC) have a long history of working with policy makers and community groups on environmental health (EH) issues. However, the infrastructure to research and fill information gaps to inform interventions does not exist. The efforts proposed by the Environmental Health Core (EHC), in collaboration with other components of the New Mexico Center for Advancement of Research, Engagement &Science on Health Disparities (NM CARES HD) establishes an intervention research agenda to reduce EH disparities based on sound research practices and informed by community needs. Our specific aims are designed to achieve this goal. Aim 1: To build on and expand existing relationships between communities, policy makers, researchers and clinicians to identify and address gaps in our understanding of EH disparities and develop an intervention science research focus in EH disparities. Aim 2: Initiate two new community partnership-based research projects, focused on interventions to reduce EH disparities. Project 1, Fiestas: Improving Food Security in an Urban Hispanic Community, will develop and pilot a collaborative community-based intervention to improve the social and food environment in an urban, food desert community with marked health disparities. Project 2, Zinc Reversal of Uranium Toxicity: Potential for Community-Based Intervention, responds to community concerns by testing a mechanism-based intervention to reverse the effects of uranium through use of zinc supplements in a prenatal cohort. Aim 3: Mentor minority trainees to develop and expand EH disparities research. We propose a vigorous, self-sustaining EHC to advance the scientific base of knowledge about interventions and solutions to socioeconomic, natural, chemical, and built environment issues contributing to the EH disparities faced by Native Americans and Hispanic communities in New Mexico.

DESCRIPTION (provided by applicant): A key objective of the INIA programs is to transform research on causes, prevention, and treatment of alcoholism. Integration of data sets and analytic methods across a broad spectrum of research is critical to success. This INIA UOI Core application is built on the success of several powerful INIA web services and data resources, including GeneNetwork, WebGestalt, and the Ontological Discovery Environment (ODE). However, our aims in this renewal are a direct outgrowth of rapid changes in genomics and neuroscience, in particular, next-generation sequencing. A theme of this core is innovation by integration. The far more pervasive use of web services in neuroscience over the last five years - Allen Brain Atlas, DAVID, ODE, Galaxy, GeneNetwork, GeneWiki, KEGG, and the Neuroscience Information Framework - represents a great research opportunity for our INIA teams. But these resources often have a steep learning curve and are difficult to use together. One of our goals is to assemble these resources together with large new data sets in a context useful to NIAAA researchers. The INIA Translational Web Services core has these aims: (1) Process, analyze, and distribute massive array and next-generation data sets for both INIA consortia; (2) Integrate INIA consortia data sets from rodents, non-human primates, and humans into GeneNetwork and significantly enhance tools for bidirectional translational queries; (3) Provide database support, training, and documentation in bioinformatics, genetics, and next-gen genomic tools to other INIA projects and cores.

Behavioral health disparities among American Indian and Alaska Native youth are dramatic, particularly in terms of depression, suicide and post-traumatic stress disorder. The goal of this proposed community based participatory research (CBPR) project is to develop and pilot test elements of a public health prevention intervention model that is tailored to be culturally and socially appropriate for adolescents on the Mescalero Apache Tribal Reservation in New Mexico. We propose to partner with a Mescalero Mental Health Prevention and Intervention Task Force to (1) identify what serious MEB problems most need to be addressed (including, provisionally, depression, suicide risk, post-traumatic stress disorder, early symptoms of psychosis and coexisting substance abuse problems ; (2) broaden the focus of existing Mescalero prevention programs to focus on a larger array of serious MEB's; (3) review and adapt screening scales for depression, suicide risk, PTSD, and early symptoms of psychosis to insure their cultural and social appropriateness for youth on the Mescalero reservation; (4) similarly review and adapt measures of symptoms resulting from contemporary and historical trauma and of desirable life function outcomes; (5) review and adapt a multifamily group (MFG) prevention treatment model to ensure its cultural and social appropriateness for youth on the Mescalero reservation; (6) conduct a one-year pilot of the feasibility of the resulting public health model (outreach, identification, referral, screening and intervention) in the Mescalero Apache School Based Health Center (SBHC); and (6) conduct a three year evaluation of the model including; a process evaluation of its ability to reach, enroll and treat the target population, obtain acceptability in the community, maintain fidelity over time to the program model, its potential for sustainability and export; and, most importantly examine outcomes in terms of student satisfaction with treatment, MEB symptom levels, quality of life impairment and clinical assessment of improvement to develop some sense of the model's potential for reducing disparities in behavioral health.

DESCRIPTION (provided by applicant): The University of New Mexico (UNM) proposes an innovative Center of Excellence titled the New Mexico Center for Advancement of Research, Engagement & Science on Health Disparities, or NM CARES HD. Based on an understanding of the common causes of health disparities across indigenous communities, NM CARES HD will apply a conceptual model that stresses three principles in interventions to eliminate those disparities: 1) community partnering, through community-based participatory research; 2) multifactoral, multilevel interventions within a cultural and social context; and, 3) translating evidence-based and community-based practice. NM CARES HD will build on the foundations of a strong set of established, collaborating institutional programs, nationally recognized expertise in several key areas, long-standing productive partnerships with Native American and Hispanic communities, and a diverse interdisciplinary collaboration to achieve its overall goal. That goal is to create a vigorous, self-sustaining, research center that advances the scientific base of knowledge about interventions and solutions to health disparities in Southwestern Native American and Hispanic communities. A strong team of investigators with senior, NIH- funded leadership has come together to meet the NM CARES HD specific aims. An Administrative Core, a Research Core, a Research Training and Education Core, and a Community Engagement Core together with two research projects will be the initial composition of the NMCOE it works toward meeting a set of specific aims and subaims. Those aims are to: 1. Establish a multidisciplinary research center that advances the science of interventions to eliminate health disparities among Southwestern Native American and Hispanic communities; 2. Enhance the ability of UNM researchers to compete for NIH individual, disparity- related research grants; 3. Build a partnership, dedicated to research on health disparities, between UNM investigators and community residents in Native American and Hispanic communities. In meeting these aims, NM CARES HD will develop innovative structures and resources to support the expansion of research on interventions to eliminate disparities in these communities. The combined resources and institutional commitments of new faculty, and pilot project and national conference support make success highly likely. RELEVANCE (See instructions):

Background: Significant health disparities exist for Hispanics and Native Americans in screening and treatment for problem alcohol and opioid use in New Mexico. Despite the availability of methods for screening and brief intervention in primary care for problem alcohol use and opioid dependence, data continue to show that such strategies are underutilized. Improved alcohol and opioid services delivery in primary care will require innovative understandings of the community and primary care context in which these services are provided. Objectives and aims: The specific aims of this ecological, mixed method project are: 1) To more fully describe the complex factors influencing implementation of evidence-based screening and treatment for problem alcohol use and opioid dependence by conducting a three-phase mixed-method study in a primary care practice-based research network; 2) To more fully understand community level factors and perceptions of alcohol use, opioid dependence and the acceptance of screening and treatment for these problems in primary care; 3) Based upon Community and Primary Care Provider feedback, create flexible models for matching approaches to alcohol and opioid screening and intervention with different primary care and community settings; and 4) To assess the feasibility of these models in enhancing screening and intervention for problem alcohol and opioid use in primary care. Design and methods: A multi-method, three phase study is planned, using survey, qualitative case study, interview, and observational data to conduct up to 12 primary care clinic assessments from which a pilot intervention study will be developed and implemented. The study will be conducted in a primary care practice-based research network and will use a participatory approach to engage community behavioral health and substance use partners. Outcomes: This study will produce data that will be used to create and test the feasibility of new model(s) for intervening in primary care clinics to enhance alcohol abuse and opioid dependence services. In contrast to previous ideas about changing primary care clinic to increase attention to problem alcohol use and opioid dependency issues, these innovative models will incorporate the situational and complex nature of primary care. Subsequent research will aim to test the effectiveness of interventions based on the new model(s) on a broader scale aimed at reducing substance use disparities among Hispanics and Native Americans.

DESCRIPTION (provided by applicant): Ethanol and stress exert a wide spectrum of neuropharmacological and neurophysiological effects that leave both molecular and cellular imprints in the CNS. While some targets of ethanol and stress in the brain have been defined, particularly shifts in neurotransmitter tone, much of the influence of ethanol is mediated by subtle and non-specific modification of allosteric interactions and downstream events that will remain hard to pinpoint and manipulate. The joint effects of ethanol and stress also vary a great deal depending on genetic differences. In this INIA renewal we will use new genomic methods to understand much more about differential vulnerability to alcohol and stress and molecular targets. We exploit a diverse group of strains of mice (BXDs) that model many aspects of human genetic complexity. In Aim 1 we evaluate predisposing differences in gene expression and splicing and the effects that individual differences have on responses to stress and to eventual alcohol consumption. In aim 2 we will study the effects of chronic intermittent ethanol exposure (and animal model of binge drinking) on voluntary alcohol consumption. Here we are asking how the combination of stress and alcohol alters gene expression patterns in an almost permanent way to induce quick relapse when access to ethanol is provided. In aim 3 we will integrate, test, and translate our results from aims 1 and 2 to understand more about the complex molecular and cellular networks that contribute to both vulnerability and allostatic changes in brain function. We will exploit extensive human data sets to test the translational relevance of finding in murine populations.

DESCRIPTION (provided by applicant): Disturbances of metabolism, often linked to mitochondrial function, have a major impact on disease risk and healthspan among human populations. Type 2 diabetes mellitus, non-alcoholic fatty liver disease, hypertension, hyperlipidemia, and cardiovascular diseases are all linked to major changes in metabolic and mitochondrial function. A complex set of genetic and environmental factors-including diet-underlie individual differences in the risk and severity of metabolic syndrome. This project is focused on the complex gene-by- environmental interactions (GXE) that contribute to mitochondrial and metabolic syndrome, and that reduce healthy lifespan. We use a new integrative systems genetics approach to study effects of a high fat Western diet. This work relies on a large family of isogenic and genetically diverse murine lines-including F1 hybrids- that serve as a translational and mechanistic bridge between reductionist and integrative approaches. Identical cohorts will be studied as a function of age on markedly different diets. In Aim 1, we study lifespan using BXD strains and non-inbred but isogenic F1 cohorts of females under high and low fat diets. We map and quantify novel GXE-type modifier loci, candidate genes, and molecular networks that modulate healthspan and longevity. In Aim 2 we generate deep molecular, mitochondrial, and metabolic biomarker data as a function of age and diet. We expect that gene variants and diet will be causally linked to mitochondrial function and to metabolism in key organs and tissues. In Aim 3 we model complex and integrative molecular and cellular networks that define differences in vitality and healthspan. We use sophisticated bioinformatic and statistical frameworks (eQTL analysis, ANOVA, and structural equation modeling). Finally, in Aim 4 we validate and translate networks involved in metabolism, mitochondria, and healthspan. We test candidate genes using gain- and loss-of-function strategies in C. elegans. We evaluate translational relevance of candidate genes and biomarkers by testing for associations in a remarkably well studied cohort of 161,000 postmenopausal women (Women's Health Initiative data sets). The WHI is an ideal translation companion to test effects of diet. This project will (1) identify high impact variants and molecular/metabolic networks involved in metabolic diseases and healthspan, and (2) provide an experimental and predictive systems biology framework that links genotype and environmental factors to disease risk in human populations.

DESCRIPTION (provided by applicant): Inhalational smoke (IS)-induced acute lung injury (ISALI) is a common clinical problem in major burn victims, contributing to the US annual burn-related death rate of 2-3 per 100,000 population, one of the highest in the developed world. ISALI is characterized by severe airway obstruction, fibrinous airway casts and debris and alveolar fibrin deposition. Airway casts are an important cause of lung dysfunction, morbidity and poor outcomes. There is no effective pharmacotherapy for this problem at this time. We have published preliminary data that shows that nebulization of tissue plasminogen activator; tPA improves lung dysfunction in our ovine model of ISALI. We have also published that perfluorocarbons (PFCs) offer unique therapeutic advantages for ISALI as they are mechanoprotective and cytoprotective, support gas exchange, and are uniformly distributed in the lung. These agents are also well-tolerated in the injured lung. We will test the hypothesis that fibrinolytic therapy appropriately delivered to airways is effective in both prevention and reversal of lung damage in ISALI. Our objective is to select the most effective fibrinolytic delivey regimen for treatment of ISALI. We will determine if a more bioavailable fibrinolysin that generates relatively lower levels of fibrinolytic activity; single chain uroknase PA (scuPA), or tPA, delivered either by nebulization or as a PFC suspension most effectively reverses lung dysfunction in ISALI in sheep. tPA is exquisitely sensitive to the major PA inhibitor in airway fluids; plasminogen activator inhibitor-1 (PAI-1), which is markedly increased in airway fluids in ISALI. Our new recently published preliminary data show that scuPA remains bioavailable via formation of PAI-1 resistant complexes with a2macroglubulin in airway fluids. Additional new preliminary formulation data show that we can create stable suspensions of fibrinolysins in PFCs and can optimize nebulization of the fibrinolysins. Our Specific Aims are: 1) To optimize formulations of tPA or scuPA-based fibrinolytic therapy for airway delivery. 2) Determine whether nebulization of tPA or scuPA or PFC-suspensions of tPA or scuPA most effectively protects against lung injury associated with ISALI and 3) To determine whether optimized airway delivery of fibrinolysins reverses lung dysfunction in established ISALI. Our team, led by experts in PFC drug delivery, ISALI, ovine modeling, fibrinolysis, drug formulation and delivery if drugs to the airway will apply a range of state of the art techniques to complete the aims. This project will likely yield novel, clinically tractable, potentially paradigm shifting approaches to safely improve outcomes in ISALI.

? DESCRIPTION (provided by applicant): The New Mexico Center for the Advancement of Research, Engagement, and Science on Health Disparities (NM CARES HD), a University of New Mexico (UNM) Center of Excellence focuses on creating health equity through intervention research that is community partnered, that is culturally- and evidence-based, and that recognizes the multi-causality of health disparities. NM CARES HD proposes a set of three pilot projects that not only embody these concepts, but also expand the scope of disparities research and the number of researchers and researchers of color engaged in disparities research at UNM. Furthermore, the pilot projects will build collaborative partnerships between NM CARES HD and two key institutional organizations: the UNM Cancer Center and the UNM Robert Wood Johnson Foundation Center for Health Policy. Each pilot project is multidisciplinary and community partnered, and collectively they bring new disciplines together in the NM CARES HD efforts. Three projects proposed are: 1) a mixed methods study with a survey to assess barriers, facilitators, and strategies to increase Hispanic participation and enrollment in health insurance under the ACA, and thereby increase access to care; 2) a qualitative, multimodal study of the relationship between home visitation program models, parent and child experiences, and the goal of reducing health disparities through enhanced early child development; 3) a qualitative, multimodal study of the barriers, facilitators and strategies to effective transition to primary cae of Hispanic and rural, underserved endometrial cancer survivors. These projects each will contribute important scientific advances to their areas of inquiry at the same time that they contribute to the goals and aims of the NM CARES HD. They also build the foundations for next steps of research in each area with specific plans outlined in the proposal.

Addiction is a highly complex disease with risk factors that include genetic variants and differences in development, sex, and environment. The long term potential of precision medicine to improve drug treatment and prevention depends on gaining a much better understanding how genetics, drugs, brain cells, and neuronal circuitry interact to influence behavior. There are serious technical barriers that prevent researchers and clinicians from incorporating more powerful computational and predictive methods in addiction research. The purpose of the NIDA P30 Core Center of Excellence in Omics, Systems Genetics, and the Addictome is to empower and train researchers supported by NIH, NIDA, NIAAA, and other federal and state institutions to use more quantitative and testable ways to analyze genetic, epigenetic, and the environmental factors that influence drug abuse risk and treatment. The Administrative Core manages relations among research cores, groups of users, trainees, and pilot program participants. The Transcriptome Informatics and Mechanisms research core assembles and analyzes hundreds of large genome (DNA) and transcriptome (RNA) datasets for experimental rodent (rat) models of addiction. The Systems Analytics and Modeling research core, is using innovative systems genetics methods (gene mapping) to understand the linkage between DNA differences, environmental risks such as stress, and the differential risk of drug abuse and relapse. The Pilot core is catalyzing new collaborations among young investigator in the field of addiction research. In sum the Center is a national resource for more reproducible research in addiction. We are centralizing, archiving, distributing, analyzing and integrating high quality data, metadata, using open software systems in collaboration with many other teams of researchers. Our goal is to help build toward an NIDA Addictome Portal that will include all genomic research relevant to addiction research.

Addiction is a highly complex disease with risk factors that include genetic variants and differences in development, sex, and environment. The long term potential of precision medicine to improve drug treatment and prevention depends on gaining a much better understanding how genetics, drugs, brain cells, and neuronal circuitry interact to influence behavior. There are serious technical barriers that prevent researchers and clinicians from incorporating more powerful computational and predictive methods in addiction research. The purpose of the NIDA P30 Core Center of Excellence in Omics, Systems Genetics, and the Addictome is to empower and train researchers supported by NIH, NIDA, NIAAA, and other federal and state institutions to use more quantitative and testable ways to analyze genetic, epigenetic, and the environmental factors that influence drug abuse risk and treatment. In the Transcriptome Informatics and Mechanisms research core we assemble and upgrade hundreds of large genome (DNA) and transcriptome (RNA) datasets for experimental rodent (rat) models of addiction. In the Systems Analytics and Modeling research core, we are using innovative systems genetics methods (gene mapping) to understand the linkage between DNA differences, environmental risks such as stress, and the differential risk of drug abuse and relapse. Our Pilot core is catalyzing new collaborations among young investigator in the field of addiction research. In sum the Center is a national resource for more reproducible research in addiction. We are centralizing, archiving, distributing, analyzing and integrating high quality data, metadata, using open software systems in collaboration with many other teams of researchers. Our goal is to help build toward an NIDA Addictome Portal that will include all genomic research relevant to addiction research.

Addiction is a highly complex disease with risk factors that include genetic variants and differences in development, sex, and environment. The long term potential of precision medicine to improve drug treatment and prevention depends on gaining a much better understanding how genetics, drugs, brain cells, and neuronal circuitry interact to influence behavior. There are serious technical barriers that prevent researchers and clinicians from incorporating more powerful computational and predictive methods in addiction research. The purpose of the NIDA P30 Core Center of Excellence in Omics, Systems Genetics, and the Addictome is to empower and train researchers supported by NIH, NIDA, NIAAA, and other federal and state institutions to use more quantitative and testable ways to analyze genetic, epigenetic, and the environmental factors that influence drug abuse risk and treatment. Our Pilot core is catalyzing new collaborations among early career investigators in the field of addiction research. In sum the Center is a national resource for reproducible research in addiction. We are centralizing, archiving, distributing, analyzing and integrating high quality data, metadata, using open software systems in collaboration with many other teams of researchers. Our goal is to help build toward an NIDA Addictome Portal that will include all genomic research relevant to addiction research.

The steady rise in prescription opioids such as oxycodone has led to widespread abuse and deaths in the US. importance of drug pharmacokinetics in determining abuse potential, we have designed an oral operant rat self-administration (SA) procedure to model the pattern of drug intake of most human users/abusers of oxycodone, who initiate using oral tablets. Although genetic variants play important roles in susceptibility to opioid addiction, very limited data are available regarding specific genes and sequence variants that predispose to opioid addiction, and under what conditions. Given the We propose to use an innovative hybrid rat diversity panel (HRDP), which consists of 91 diverse rat genomes, to identify genetic variants influencing operant oxycodone intake in rats. The HRDP is unique in that it: 1) contains a high level of genetic diversity similar to that of human populations; 2) provides a way to control oxycodone exposure and to systematically study gene-by-environment and gene-by-drug interactions; and 3) integrates multi-omics addictome data: from genetics to epigenomics to brain connectomes to treatments. We have three aims: Aim 1: We will analyze whole genome sequencing data to define virtually all sequence variants that underlie heritable variations. De novo assemblies will be conducted using linked-reads data for selected high impact strains. Hi-C data (Dovetail Genomics) will be generated to further improve the quality of these assemblies. We will also generate RNA-seq data for key brain regions to obtain mechanistic insights into oxycodone intake. Aim 2: Using the HRDP (both sexes), we will phenotype oral oxycodone SA with a unique behavioral model. Rats will also be tested for sensitivity to pain, social behaviors, and anxiety-like traits - all signs of oxycodone withdrawal. Critically, we estimated the heritability (h2) of oxycodone intake in the range of 0.3 ? 0.4. When using n=6/sex, the effective h2 is ~0.8 ?sufficient for high precision mapping. Aim 3: We will use systems genetics methods to map and integrate behavioral phenotypes with sequence and transcriptome data. Both forward (QTL) and reverse (PheWAS) genetic methods will be used. We use new linear mixed models to map and test candidate genes with key cofactors using the GeneNetwork2 platform. Finally, we evaluate the translational relevance of candidate genes and biomarkers by comparison to GWAS cohorts and longitudinal reports of addiction in humans. Technical and conceptual advances that underlie this application are: new genomic methods combined with highly diverse rat populations allow us to quickly define novel gene variants that modulate key phases of opiate addiction. It is highly likely that a subset of variants and molecular networks we define will provide key components of a predictive framework linking sequence differences to human opioid addiction and potential treatments. This project uses new systems genetics approaches, open source genomic data and software, and a new type of hybrid rodent mapping panel to precisely define causal linkages between DNA variation and voluntary oxycodone intake.

Age-related cognitive decline (ARCD), Alzheimer disease (AD), and late-onset AD-related pathologies are linked to changes in brain structure, cell populations, synapse densities and connections, inflammation, protein aggregation and mitochondrial stress. However, we do not understand the complex causal networks and mechanisms of ARCD and AD. In this neurogenetics imaging program we quantify the impact of human familial AD (FAD) gene variants on brain structure and function using a highly diverse cohort of aging mouse hybrids that combine human genes variants with the BXD family. In Aims 1 and 2 we generate high resolution whole brain MRI DTI data and connectomes for each of 40 sex-matched sets of transgenic and aging control hybrids at ~6 and ~14 months using state-of-the art analysis workflows. We generate matched behavioral data, as well as light-sheet immunohistochemistry for entire brains taken from subsets of cases with the most outstanding phenotypes?lines that are highly susceptible to cognitive loss and those that are most resilient. Light-sheet, MRI-DTI and fMRI connectomes is merged with MI-DTI in Aim 3. All work exploits systems genetics and mapping methods we have developed and embedded in the GeneNetwork web service. A crucial facet of Aim 3 is integrating extensive behavioral data on age-related cognitive and other behavioral and CNS changes generated from AD-BXD and many other models. This allows us to define loci, candidate genes, and mechanisms modulating ARCD and AD, and to systematically test for associations with age, sex, and linked changes in structure, connectivity, and cell types. Finally, we integrate omics data we have for BXD and other genomes (e.g., hippocampal RNA-seq and proteomes) with comprehensive human AD GWAS, imaging, and omics data. All results are shared openly using robust internet services?GeneWeaver, CIVM server, NIF, Mouse Phenome Database, and the AMP-AD Knowledge Portal. Data and workflows will be FAIR-compliant. Key deliverables are (1) far more quantitative, unbiased, global, and replicable data on genetic, molecular, cellular, and system-wide processes linked to cognitive loss and AD. We also deliver causal molecular and mechanistic models of that incorporate realistically high levels of genetic diversity?6 million DNA variants. This work empowers in-depth unbiased analyses of age-related functional decline in ARCD and AD that translate to human populations. Success will enable faster and more robust preclinical testing of interventions and drug treatments for ARCD and AD.