John Wood - US grants

The investigators will pursue research in various areas of differential topology, differential geometry, and algebraic geometry. More specifically: 1) John Wood will study the topological, differential, and complex structure of algebraic manifolds, especially questions on deformations and analytic embedding. 2) James Heitsch will continue his study of the geometry of foliations and the extension of the theory of analytic invariants to foliated manifolds. 3) Anatoly Libgober will study the topology of algebraic varieties, especially questions on the structure of the complement of branching loci and its relation to problems of classification up to deformation.

The major emphasis of this research project deals with the mechanisms of substrate-induced homolytic cleavage of the Co-C Female bond in B12-coenzyme catalysis. Model studies with methylcobalamin demonstrate that homolysis of the Co-C bond occurs in the transfer of methyl-groups to CrII, SnII as well as to PtII/PtIV complexes. Also, we have shown that homolysis occurs in a methyl-transfer to coenzyme M (ethanethiol sulfonic acid) by a B12-dependent transmethylase purified from cell-extracts of Methanosarcina barkeri grown on methanol as sole carbon source. Using a variety of spectroscopic techniques, we have obtained preliminary evidence that the formation of a "charge-transfer" complex between substrate and the corrin macrocycle precedes homolysis of the Co-C bond. Therefore, complexation of the substrate with the corrin-ring occurs, rather than direct attack on the Co-C bond. These new results indicate that electrophiles can react with B12-coenzymes either by direct attack at the Co-C bond (i.e. SE2 mechanism) (e.g. HgII, PbIV, TlIII and PdII); or by reacting as oxidants through complexation with the corrin ring. (e.g. IrIV, PtII-X-PtIV and FeIII). The rate-determining step for the latter reaction appears to involve a one-electron transfer from the corrin ring to the complexed electrophile. Since homolytic cleavage of the Co-C bond occurs in a number of B12-enzyme catalyzed reactions, and since this mechanism is not fully understood, we intend to expand our study of reaction intermediates in B12-dependent methyl-transfer to platinum salts, and to coenzyme M by the transmethylase which we have purified from M. barkeri. A similar B12-dependent transmethylase is implicated in C1-metabolism in Clostridium thermoacticum (1). This organism synthesizes acetyl CoA from carbon monoxide and coenzyme A. Using 13C NMR in a wide bore 360 MHz NMR spectrometer we intend to perform a comparative study of autotrophic metabolism on C1 compounds, by using 13C enriched substrates for M. barkeri (i.e. 13CH3OH, 13HCOOH and 13CO) and for C. thermoaceticum (13CO and 13CO2). The role of B12 in whole cells, and at the enzyme level, will be studied in an effort to delineate the metabolic pathways for the autotrophic growth of anaerobes on C1 compounds.

The major objectives of this research are: 1) to continue our studies to characterize components of specialized cisternae of endoplasmic reticulum which are lined with carbohydrates and which very likely serve as a transport system in neuronal processes; and 2) to continue a portion of our studies to relate the localization of macromolecules to the expression of different functions performed by neurons and glia. Macromolecules of nervous tissue membranes will be localized by: 1) the use of specific lectins which bind to different sugars and toxins which bind to specific receptors in combination with peroxidase labeling techniques to visualize sites of such binding; and 2) the use of antisera to specific brain macromolecules together with peroxidase conjugated antibodies to visualize tissue sites containing these macromolecules. These experiments will be performed on normal tissue and tissue in which axonal transport is blocked by a local cooling method. We will continue to characterize potential candidates for glycoproteins lining the specialized smooth membrane cisternae using lectin affinity chromatography, gel electrophoresis and immunocytochemical procedures. Antisera to those glycoproteins which do line the smooth membrane cisternae will be used in experiments to determine if transport is blocked when specific carbohydrates lining the cisternae are complexed with antibody protein. The possible involvement of carbohydrate lined cisternae in transport will be tested further by studying whether or not specific membrane probes will be taken up by neurons and become associated with the cisternae during transport and what factors influence both uptake into the cell and association of the probes with the cisternae. The role of coated vesicle proteins and other structural proteins such as Alpha-actinin in transport (particularly retrograde transport) will be studied using immunocyto-chemical methods to localize specialized regions of the synaptic terminal containing these proteins, and using antisera to the proteins to test their effect on blockage of cellular uptake of macromolecules and/or subsequent retrograde transport of the molecules.

The long term objectives of this research program are to understand the mechanisms by which the cytoskeleton becomes abnormal in Alzheimer's diesease and, perhaps, in normal aged brains. We are particularly interested in the role phosphorylation of cytoskeletal polypeptides might play in mediating the ability of the polypeptides to interact in an appropriate fashion to form noraml cytoskeletal organelles. A major hypothesis we will be testing is that alterations in the state of phosphorylation of cytoskeletal polypeptides in Alzheimer's disease is one step leading to the formation of the paired helical filaments (PHF) in the neurofibrillary tangle (NFT) and neuritic plague (NP) that are a hallmark of the pathology of this disease. Results to date indicate that modifications in the state of phosphorylation of the tau family of microtubule-associated proteins may be a step in the pathogenesis of the NFT and NP. In this program we will use a variety of biochemcial procedures to isolate and purify individual tau isoforms and fragments from AD brains to use in bioassay with regard to their properties in stimulating the assembly and stability of microtubules as a test for those fragments likely to contain biologically relevant modified sites. We will also compare the detailed pattern of tau cytochemistry in buffer and alkaline phosphatase treated NFT and NP at the electron microscopic level to ask whether or not sites accessible to anti-tau without dephosphorylation represent early-forming tangles with relatively unmodified tau associated with some straignt tubules, whereas those sites exposed after dephosphorylation represent tau modified by more extensive phosphorylation to participate in the formation of networks of PHF. We will use phosphorylation by exogenous and endogenous protein kinase activities of tissue sections and membrane blots to further identify and characterize sites on the tau family of polypeptides which might be modified in AD and, potentially, in aged human brains.

This is a Research Equipment Grant for reactive-ion-etcher/PECVD/RF- sputtering equipment to be used in research on microelectromechanical devices. This research project focuses on the design, analysis, and fabrication of devices with single or numerous micron-scale internal components forming either moveable mechanical elements, which are actuated by strong fields, or sensor elements, which infer relative positions of components based on local fields. Devices to be produced using this equipment include sensors -- such as strain gauges, micropositioners, and multi-axis tactile sensors -- spatial light modulators, and actuators. Crucial to the design of these devices is the ability to build deep or complete cut-outs into the structure, and to pattern metals, insulator and magnetic materials. This equipment will allow the on-site generation of microelectromechanical devices requiring vertical etching principally in silicon-based materials, and the generation of such devices requiring deposition of conductors, insulators, and magnetic films.

This project will provide assistance to academic personnel who are engaged in Microelectromechanical systems research by providing travel funds to attend the 1989 IEEE Micro Electromechanical Systems Workshop, to be held in Salt Lake City on 20-22 February 1989. An announcement in response to workshop registrations will be made to notify participants of the availability of support. A committee of six senior researchers in the field will select the candidates for travel and subsistence assistance awards. The awards will seek to encourage innovative research and special consideration will be given to aiding young researchers in the field. The following set of priorities will be used in making the awards: First Priority - graduate students who are presenting papers; Second Priority - researchers less than 5 years beyond their doctorates who are presenting papers; Third Priority - researchers having a proven record of productivity in the area and who can justify a genuine need for travel assistance. In order to stretch the available funds, partial travel grants will be considered. All support will be used to aid attendees from the U.S.

During the past 25 years, instrumentation use in chemical analysis has changed dramatically. The rapid development of mass spectroscopic analysis for example, has been made possible by advances in computer interfacing, gas chromatography, and quadrupole mass detection systems. Since mass spectroscopy analysis has become a routine indispensable tool for identifying organic substances, it is essential that students majoring in laboratory sciences gain experiences with this technique. This project enables IUP to implement these goals. The experiments done by the students allow them to become more proficient in using the mass spectrometer and in interpreting data produced by this instrument. This instrument is also used in other laboratory disciplines including Biology, Medical Technology, Criminology, and Safety Science. The institution is matching the NSF grant with an equal amount of funds.

This grant will provide support for graduate students and young facultywho do not have alternative means of support to attend the Third IEEE Workshop on Micro Electro Mechanical Systems, to be held at Nappa Valley, California, February 12-14, 1990. This workshop is the premier workshop of this emerging field, and it has contributed to the rapid advance of the field. This support will enable many young researchers who are just beginning research in the filed to attend. It is important because the field is so new that researchers have yet to establish funding that would enable them to attend the workshop without this grant.

The ultimate goal of the experiments proposed herein is to identify tyrosine kinase substrates and their function in developing and mature brain. Affinity purified polyclonal antibodies to phosphotyrosine will be used to determine the dynamics of tyrosine phosphorylation at cellular, subcellular and substrate levels. Previous immunohistochemical studies indicate that the majority of tyrosine phosphorylation detectable by these methods is in microglia and is associated with growing axons. The primary focus will be on establishing which proteins are tyrosine-phosphorylated in these two compartments, and on determining their subcellular location. Two tyrosine kinase substrates in cerebellar homogenates (135 and 95 kD) have a developmental pattern of phosphotyrosine-immunoreactivity coincident with that of axonal growth in the cerebellum. Consequently, antibodies will be generated to these two species for use in cellular and subcellular localization experiments to determine whether these may be axonal growth-associated proteins (GAPs). As an alternative approach, GAPs in developing optic nerve will be probed with anti-phosphotyrosine antibodies for the presence of these or other tyrosine kinase substrates. To investigate the second phosphotyrosine- immunoreactive compartment, experiments are proposed to determine the tyrosine kinase substrates of primary cultures enriched in microglia. Established in vitro protocols will enable a study of the dynamics of tyrosine phosphorylation during microglial proliferation, differentiation, activation and subsequent secretion of glial promoting factors (GFPs). The inability of CNS neurons to regenerate may be due to the formation of glial scars, which might discourage axon growth and are formed at least in part through the action of microglial GPFs. As the preliminary data suggests tyrosine phosphorylation occurs in growing axons and microglia, the information gathered in the proposed experiments has the potential to promote our understanding of and ability to influence repair mechanisms in the CNS.

DESCRIPTION The ultimate goal of this research is to understand mechanisms underlying the interactive role of microglia and neurons in neuronal injury and neurodegenerative disease. The unifying theme is the reciprocal regulation of protein phosphorylation systems in microglia and neurons in neuronal injury and neurodegenerative disease regarding key early events governing the functional response of each cell type, and thus represent critical therapeutic intervention points. The specific hypotheses addressed are that regulation of microglial tyrosine phosphorylation is a seminal and necessary step in the response of microglia to neuronal injury, and that microglia activated by amyloid peptides secrete soluble factors which mediate phosphorylation of neuronal tau proteins to an AD like state via identifiable potentially novel pathways. An animal model of neuronal degeneration in which microglia exhibit a robust upregulation of tyrosine phosphorylation prior to any other sign of activation, together with infusion of tyrosine kinase inhibitors, will be used to ask whether blocking tyrosine phosphorylation prevents the conversion of microglia from the ramified to the ameboid form. Western blot and in gel kinase analyses will be used to examine the dynamics, substrates and enzymes involved in this response Hippocampal neurons in culture will be used to examine regulation of tau phosphorylation by factors derived from microglia activated in the presence of amyloid peptides. Current data indicate that this phosphorylation may be effected by novel kinases, and Western blot and in gel kinase assays will be used to confirm and extend these results. Kinase inhibitors will be used to ask whether release of microglial factors is dependent on tyrosine phosphorylation.

This grant will support a multi-agency workshop on microelectromechanical systems (MEMS). The purpose of the workshop is to introduce MEMS to a broad range of Federal agencies, and to seek applications of the technology in the solution of problems faced by these agencies. Three specific objectives of the workshop are (1) to introduce MEMS to representatives of several Federal agencies, (2) to identify MEMS applications relevant to these agencies, and (3) to provide a high-quality report on the status of MEMS technology and a prediction of future developments and applications.

An ultramicrotome is requested to help investigate cellular polarity and subcompartmentation. One project uses a developmental approach to dissect the various mechanisms that polarize the distribution of membrane proteins in simple, transporting epithelia. Another project examines the ordered arrangement of 3 isoforms of dynein associated with the microtubules of flagella in Chlamydomonas. This arrangement is required for flagellar bending. Two projects examine the polarity of the neuron. The first addresses the polarized distribution of the 5 -tubulin isotypes presumably confers different functions to different classes of microtubules. The second project examines the polarized distribution of tyrosine kinases, isoforms of protein kinase C, and their substrates. Ultramicrotomy is central to all of these projects. Standard transmission electron microscopy is require to relate the structure of reconstituted axonemes, or axonemes isolated from mutants with defective flagella, with their behavior in functional assays. In the other projects, proteins of interest will be localized by immunocytochemistry at the light level (using immunocluorescence staining of 0.5-1.0 M frozen thin sections) or at the electron microscopic level ( using immunogold and immunoperoxidase methods).

tau proteins; protein structure function; phosphorylation; molecular pathology; Alzheimer's disease; protein isoforms; paired helical filament; protein tyrosine kinase; cytoskeleton; microtubules; protein sequence; amyloid proteins; immunochemistry; fluorescent dye /probe; laboratory rat; microinjections;

9708221 Insana Quantitative ultrasound (QUS) techniques are to be developed to detect early changes in renal microstructure that ultimately lead to end-stage renal disease (ESRD). QUS involves analysis of echo spectra in frequency channels corresponding to scattering from various anatomical scales to measure the size, number density, and collagen content of essential tissue microstructures. These are among the first techniques for analyzing histological properties of tissues in vivo and noninvasively. The incidence of ESRD in the United States is increasing geometrically. Average medicare costs were $46,117 per ESRD patient for a total of $9.5 billion in 1992. A definitive diagnosis of progressive injury leading to ESRD is now based on clinical findings and biopsy; that often occur late in the disease process. Currently no test exists to establish the presence of early kidney injury or to identify populations at risk for whom prevention of progressive injury should be attempted. This investigation will examine the potential of QUS as a safe, inexpensive, and noninvasive method for early detection of renal injury caused by several common conditions including diabetes, hypertension, and cystic kidney disease. This three-year, multidisciplinary research project aims to develop new biomedical instrumentation, experimental techniques, and models of disease processes. If QUS can successfully identify patients at risk for ESRD, the potential to prevent disease would be improved, the net cost of treating the disease would be reduced significantly, and the quality of life for those patients affected would be improved. This research program is part of a new graduate-level Biomedical Engineering Program at the University of Kansas. ***

DESCRIPTION: The PI reports that the disruption of cellular signal transduction via protein kinase (PK) malfunction has been related to the onset of several disease states, including: rheumatoid arthritis, systemic lupus erythematosis, diabetes mellitus, and Alzheimer's disease. He notes that while PK inhibition is a logical target for chemotherapeutic intervention, the structural homology among the many PK isozymes has impeded the development of specific and hence therapeutically useful inhibitors. It is indicated that some specificity has been achieved in the area of indolocarbazoles and hence the archetypal naturally occurring congeners staurosporine (1) and K252a (2) have been the focus of considerable research. The PI states that this proposal describes: (A) preliminary studies in which a concise synthesis of 2 has been achieved (eleven synthetic operations, longest linear sequence of seven steps); and (B) the application of this chemistry to the synthesis of 1 and analogs of 2 (i.e., 3). It is reported that the latter analogs are targeted for use as probes in a Chinese Hamster Ovary Cell assay developed at Yale and the capping agent in a combinatorial peptide library that can be utilized to screen a wide range of analogs for PK isozyme specificity. It is noted that finally, efforts toward K252a have resulted in the development of novel carbenoid reactions for which further research is proposed.

The semiconductor (S/C) manufacturing sector of the U.S. economy is growing rapidly. However, the ability to supply a well-trained workforce for this major economic sector is severely lagging the demand. Furthermore, as the technical and role demands for technicians increase, their core knowledge in the areas of statistics and unit-process operations increasingly overlaps that of engineers in an S/C plant. Conversely, new engineers, who may become responsible for technician oversight in a factory setting, need to better understand the job scope of technicians, as well as receive more hands-on training during their academic program. It is thus advantageous to cross-train S/C engineers and technicians in shared factory-like settings for selected equipment-intensive courses, without artificially forcing complete articulation between respective curricula. Such side-by-side training, broken into unit modules, decreases per-student lab costs, and thus training costs, while also facilitating: (1) cross-training of existing factory technicians and engineers, for lifelong learning, (2) cross-training of community college and university faculty, and (3) academic migration of technicians who later choose to pursue engineering careers. In this project, a consortium of three universities and three community college systems in three contiguous states, each having S/C manufacturing as an economic backdrop, is facilitating side-by-side training of technicians and engineers, bolstered by the development, utilization, and evaluation of computer-aided curriculum modules to be integrated into factory-like labs and related courses. These modules will cover S/C unit processes and their facility demands from both technician and engineering perspectives. The multimedia modules are being designed to function either independently or coupled to a multilevel manufacturing simulator package. They can serve training needs in real, mock, or virtual factory-like labs, or they can be used for assessment.

The project extends work begun under Award No. 9850310.

A consortium consisting of three universities (University of New Mexico, Arizona State University, and University of Texas at Austin) and three community college systems (Albuquerque Technical Vocational Institute, Maricopa County Community College District, and Austin Community College) in three contiguous states, each of which has semiconductor manufacturing as an economic backdrop, is implementing "cross-training" of technicians and engineers.

Supported by a previous NSF grant, the consortium developed a suite of six computer-based training (CBT) modules designed to be integrated into factory-like labs and related courses for co-training of technicians and engineers. The first six modules covered lithography, metalization, design of experiments, etch, chemical vapor deposition, and statistical process control. In the current project, the consortium is (1) developing three more modules covering oxidation and diffusion, doping and annealing, and factory dynamics; (2) deploying the modules in side-by-side training of engineering and technician students at the partnering universities and community colleges; and (3) completing the evaluation of the full suite of nine modules.

The project is built around the premise that "cross-training" technicians and engineers, such that each group better understands the roles and skill sets of the other, will enhance their effectiveness as team members in real factory settings. The project's CBT modules cover basic semiconductor unit processes (lithography, metalization, etch) and their facility demands, design of experiments, and factory-level dynamics from both the technician's and the engineer's perspectives. The modules include interactive, schematic-based simulator panels for selected manufacturing machines, to support a need-based, top-down learning paradigm. In addition, the modules have structured exercises that require interactive roles between technicians and engineers. The "side-by-side" presentation of text, graphics, animations, videos, simulations, and exercises give technicians enhanced exposure to mathematics and science and give engineers enhanced exposure to machine (tool) operation issues. The multimedia modules are designed to operate stand-alone or coupled to a multi-level manufacturing simulator package. They can serve training needs in real, mock, or virtual factory-like labs.

Efforts to prepare naturally occurring molecules of biological importance are extremely valuable to health sciences in the United States. Firstly, these efforts provide an exceptional training ground for scientist who will develop the next generation of important drugs. Second, these efforts always provide a unique means of accessing structure activity relationship data for the natural products themselves and compounds in similar structural classes. Thirdly, these efforts always result in the development of new strategies and chemistry that can be used for the synthesis of complex molecules. This proposal describes three such synthetic efforts. The most mature is directed toward a class of squalene synthase inhibitors known as the phomoidrides. Efforts in this area have spawned new chemistry in the field of aryl oxidation; further developments in this area are proposed along with a second synthetic effort directed toward ryanodol, an important calcium channel blocker. Finally, a fruitful collaborative effort looking at the biology of alpha, beta-epoxy ketone-containing natural products is described that is destined to provide important biological information about molecules in the sorbicillin class.

DESCRIPTION (provided by applicant): In neurodegenerative conditions such as Alzheimer's disease (AD), the tau family of proteins are displaced from their normal association with microtubules and form into paired helical filaments (PHF) that are the hallmark cytoskeletal pathology of the disease. The degree of this pathology correlates closely with the clinical severity of AD. Several posttranslational modifications of tau, including phosphorylation, have been implicated in AD pathogenesis. In addition, and importantly, actual mutations in the genes encoding human tau have recently been implicated in a variety of hereditary dementias, collectively termed frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). This has rekindled interest in the importance of tau in neurodegenerative diseases. Despite significant progress in the field of tau biology and neurodegenerative diseases, several important issues remain unresolved. The early functional consequences of tau alterations in living neurons is incompletely understood, and it is not clear how tau in neurodegenerative diseases becomes redistributed from its normal concentration in neuronal axons to pathological inclusions in neuronal soma known as neurofibrillary tangles (NFT). One of the reasons for these gaps in knowledge is the relative paucity of model systems to study these processes. We propose to develop a transgenic model system, including germ line transmission, to study the functional consequences and trafficking patterns of human tau either mutated on sites associated with hereditary dementias or altered at select posttranslational modification sites and expressed in zebrafish neurons. Molecular biological protocols will be used to prepare normal and mutated human tau green fluorescent protein (ht-GFP) constructs under control of the neuron specific zebrafish GATA-2 promoter. The constructs are expressed after microinjection into zebrafish embryos or identified neurons later in development. Cell health, development, tau trafficking patterns and filament formation will be examined and related to both the type of tau mutation being expressed as well as to the expressed tau phosphorylation status. The overall guiding hypothesis is that the model allows dissection of a hierarchy of events relevant to potential mechanisms of neurodegenerative diseases related to critical early stages in development of disease. The model should prove very useful as well in future gene array assays to identify specific genes turned on or off at critical times in the early reorganization of FTDP-17 mutant taus identified from real time microscopic analyses. In addition, the approaches developed here will have broad usefulness in the study of functional consequences and potential genetic analyses of introducing into living vertebrate neurons other molecules involved in the pathogenesis of neurodegenerative diseases.

The Albuquerque region is home to large government laboratories, large technical industries and many small high technology companies. The Southwest Center for Microsystem Education (SCME), a collaboration of the University of New Mexico, Central New Mexico Community College (CNM) , and the Southwest Indian Polytechnic Institute (SIPI), increases the educational capacity of the region to produce technicians skilled in supporting microelectromechanical system (MEMS) research, design, and commercialization. The regional center builds on its previous work to establish workforce needs and standards to engage academia, industry and government in identifying microsystem technician competencies, while also increasing awareness of career opportunities in MEMS by community college and high school students. Based on a needs assessment and building on prior experience, learning modules and kits are developed to enhance microsystem-focused programs and curricula in high schools and community colleges. Thirty more shared-content object (SCO) suites are created to support new topics in MEMS fabrication, characterization, instrumentation and career exploration. Hands-on kits that bring elements of the cleanroom fabrication experience into the classroom are developed and disseminated. The Center continues to provide professional development workshops for high school, community college and four-year college faculty. Each year four one-day introductory awareness workshops and four five-day cleanroom short courses are offered - one workshop is offered to tribal colleges. The Center increases interest in MEMS in high-school age populations by working in high schools that have large numbers of students from underrepresented groups and with their teachers. The effectiveness of the materials and professional development is evaluated.

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. The purpose of this study is to determine the relationship between cardiac function, exercise capacity, and cardiac rhythm to cardiac and liver iron loading. Eighty patients with various stages of iron overload will have a full, clinical cardiology evaluation (ECG, Echo, stress exercise and Holter monitoring) and a research MRI study (to quantify liver and myocardial iron and cardiac function). These studies may lead to 1) normative data for cardiac rhythm and performance for thalassemia patients, 2) determination of the prevalence of exercise and cardiac rhythm abnormalities in thalassemia patients with high cardiac iron and normal resting function, and 3) determination of the relationships between liver iron content, ferritin, cardiac T2* and cardiac function. These studies will provide the necessary groundwork for longitudinal studies of cardiac iron load on cardiac performance in thalassmia patients. The results of this study may lead to improved, early recognition of pre-clinical iron cardiomyopathy.

The University of New Mexico (UNM), a Carnegie Doctoral/Research University-Extensive and a Hispanic-serving Institution, is building a cleanroom within its Manufacturing Training and Technology Center (MTTC), to support research, training and commercialization of microelectronics and microelectromechanical systems (MEMS). The cleanroom has received construction funding from federal and state sources, and major equipment from private sector sources. The deep reactive ion etcher, and the parylene coater provided by NSF MRI will enable the cleanroom to support not only conventional semiconductor processes, but to also support fabrication of bio- microelectromechanical systems (bio-MEMS). In particular, this equipment will allow UNM to make bio-MEMS devices with deep channels, for example, and biocompatible coatings needed for implantable devices. Specific devices might include implantable drug delivery devices, micro-scale ultrasound emitters and detectors for more localized imaging, micro-scale cancer treatment probes, photonics-based cell sorters, and micro-motors on a chip. Applications will extend to the diagnosis and treatment of human disease, sensors and actuators needed for space missions, or monitoring of environmental pollutants, toxins and infectious agents. In addition to research and development support, the requested equipment, set within the MTTC Cleanroom, will be available to co-train a diverse population of engineering students at UNM with technicians from regional community colleges (CCs). And, the equipment will be available for private companies to prove the manufacturability of a device prior to large-scale manufacturing.

This award from the Synthesis Program will support a "Workshop on Organic Synthesis and Natural Products Chemistry." This workshop has the dual purpose of providing an effective forum for informal discussion among young academic and industrial scientists on current research in topical areas of organic synthesis and natural products, and assisting the Program staff in identifying emerging areas and researchers. This process, in turn, will aid the Program in long-range planning. The specific goals of the workshop include: 1) Providing an environment for the dynamic exchange of ideas in organic synthesis, natural products, and bioorganic chemistry. 2) Encouraging an attitude of cooperation among individuals working in related areas, and thereby, avoiding duplicative efforts. 3) Stimulating participants to study new problems and methods in synthetic and natural products chemistry. 4) Improving awareness of potentially valuable applications of new methods and strategies in synthesis. 5) Increasing diversity at high-level meetings. 6) Creating an atmosphere in which the scientific and social interaction among participants will be both stimulating and pleasant.

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. Pulmonary hypertension (high blood pressure in the lungs) is a leading killer in patients with sickle cell disease (SCD). Regular blood transfusions improve many aspects of SCD but it is not known whether they help prevent pulmonary hypertension. We will examine this question two ways. First, we will compare the degree of pulmonary hypertension in regularly transfused patients with SCD to those who do not receive transfusions;if the transfused patients have significant less pulmonary hypertension it suggests that transfusions are protective. Secondly, we will examine chronically transfused SCD patients before and 72 hours after having a blood transfusion to see if the transfusion acutely changes the blood pressure in the lungs. In addition to looking at lung blood pressure, we will examine the contraction and relaxation of the heart, heart rate variability (an indirect sign of heart health), blood vessel relaxation, volume of blood pumped by the heart, blood oxygenation, and the integrity of the red blood cells as these variables are all associated with changes in lung blood pressure. Specific Aim 1: Determine the prevalence of pulmonary hypertension and endothelial dysfunction in a group of patients with sickle cell anemia on chronic transfusion therapy. Specific Aim 2: Identify predictors of pulmonary hypertension and endothelial dysfunction in the subgroup of patients with sickle cell anemia on chronic transfusion therapy. Specific Aim 3: Identify acute effects of transfusion therapy on TR jet velocity, hemolysis, hypoxia, cardiac diastolic function, and endothelial function.

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. The purpose of this experiment is to determine whether pancreatic iron, liver iron, or both predict insulin resistance and impaired islet cell function in thalassemia major patients. To address these aims, this experiment will ask patients to undergo MRI liver and pancreatic iron assessment (or use values from their clinical scans) and to participate in either an oral glucose tolerance test or single fasting glucose assessment. The goal is to improve preclinical recognition of diabetes in iron overloaded patients.

This application describes the development, progress, and future directions of several projects dedicated to the synthesis of physiologically important natural products, as well as the investigation of an interesting reaction discovered through these efforts. The primary goals of each project are the development and application of methods to complete the synthesis of the desired targets. The current strategies for the synthesis of these targets have been designed to be amenable to the incorporation of alternative functionality for the development of analogs, which will be subjected to biological screening to identify novel or interesting physiological activity

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
This is a new 18-month Science Master's degree in NanoScience and MicroSystems. The program curriculum is providing students with the knowledge and skill to turn breakthroughs in nanoscience into innovative commercial technology. It uses project-based learning as a method for integrating education, research, and training in nanotechnology. It targets the needs of employers by preparing graduates for careers in nanotechnology with local and national start-up companies and established firms.

Through a partnership with the Management of Technology program located within University of New Mexico's Anderson School of Management, students are learning skills in finance, marketing, communication, and project management needed to bring new technology to the marketplace. Entrepreneurship is developed through cohort-based participation in the University of New Mexico's Business Plan Competition.

Broader Impact: Nanoscience is an important base of support for key industries in the 21st century. New Mexico is recognized as a center of nanotechnology research and entrepreneurship. The University of New Mexico is Hispanic-Serving and classified by the Carnegie Foundation as a research university with very high research activity. Competitively awarded stipends will be available to the first two student cohorts, helping to ensure broad access to this degree. Internships and research experiences will be tied to the needs of local and national industry and government labs. Upon completion of this degree program, students will be prepared for careers and leadership positions in nanotechnology.

With this award, the Chemical Synthesis Program is supporting Professor John L. Wood of the Department of Chemistry at Colorado State University to develop new methods for the formation of oxygen- and nitrogen-containing heterocycles via a rhodium(II)-mediated O-H/N-H insertion tandem Conia-ene cyclization. Since its discovery, the Conia-ene cyclization has presented a method for assembling carbocycles from linear substrates containing an enol and pendant olefinic moiety. This rearrangement remains synthetically underdeveloped because of the harsh reaction conditions required for its application. Recent advances in metal-catalyzed Conia-ene cyclizations have made this reaction more amenable for synthetic use, however the reaction is still limited to underfunctionalized, linear precursors. One metal that has not been explored is rhodium(II). Rhodium(II) is well known for its dediazotization ability in carbene chemistry, but few examples exists where it behaves as a pi-Lewis acid that would help initiate a rearrangement such as a Conia-ene cyclization. Tandem reactions are synthetically attractive for their efficiency and tendency to generate minimal waste. The development of this reaction sequence will create a new synthetic tool for the construction of target compounds that possess interesting biological and structural properties including complex natural products. Specifically, the proposal outlines a strategy utilizing the newly developed method for the synthesis of the welwitindolinone B/D family. Syntheses of theses compounds could generate intermediates that possess medicinally relevant activities.

In terms of Broader Impacts, the PI will build on his notable track record in training undergraduate, graduate, and postdoctoral fellows through the scholarly pursuit of methods development and its application to the construction of complex molecular targets. It is expected that these individuals will have a positive influence on the academic community, pharmaceutical industry and allied scientific fields in the general areas of matter by design and controlled molecular synthesis.

ABSTRACT

The Southwest Center for Microsystems Education (SCME) creates and promulgates microsystems educational materials for students and professional development opportunities for educators. The goal is to improve the educational capacity of the nation to produce technicians skilled in supporting microsystems research, design and commercialization, while increasing awareness of microsystems career opportunities by diverse student populations. The Center generates educational materials and produces and disseminates hands-on kits that bring elements of the clean-room fabrication experience into the classroom. The Center provides clean-room-based professional development workshops for high school, community college and four-year college faculty and assists transfer of SCME MEMS-based short courses to other venues. SCME is a strong consortium of institutions catering to the needs of their local area with partner satellites or hubs at ND State College of Science, University of South Florida, Ivy Tech Northeast, Washington Engineering Institute, Albuquerque Public Schools, Central New Mexico CC and Southwest Indian Polytechnic Institute. SCME also collaborates with other ATE centers focused on nanotechnology, microsystems, semiconductor technology and biotechnology. More emphasis is placed on expanding SCME's reach by determining localities that have companies that require MEMS technicians and working with nearby community colleges to develop educational programs to support them.

The value of the Center is evaluated using a five cycle process: evaluation of the activities and interactions themselves; evaluation of the outcomes of the activities in terms of development of human and social capital and resources; evaluation of the changes in faculty practice and impacts on students; evaluation of the impact on the technician workforce in microsystems design, manufacturing and commercialization; and evaluation of the changes in the Center's ability to achieve what matters to it and other stakeholders.

The change in strategy moves the Center from a University of New Mexico-centered delivery strategy for faculty development to a distributed delivery system with the development of "hubs" at other educational institutions to deliver workshops and support the education of technicians for the MEMS industry in their geographic region.

With this award from the Major Research Instrumentation Program (MRI) and support from the Chemistry Research Instrumentation Program (CRIF), Professor Patrick Farmer from Baylor University and colleagues Caleb Martin, Kevin Pinney, Bryan Shaw and John Wood will acquire an electron paramagentic resonance (EPR) spectrometer. This instrument will allow research in a variety of fields such as those that provide insight on how biologically relevant species behave when they possess unpaired electrons. In general, an EPR spectrometer yields detailed information on the geometric and electronic structure of molecular and solid state materials. It may also be used to obtain information about the lifetimes of free radicals, short-lived, highly reactive species involved in valuable chemical transformations as well as the initiation of pathological tumor growth. These studies will impact a number of areas, from the synthesis of inorganic and organic molecules to the development of new solid state materials to compounds of magnetic and biological interest. Employing examples inspired from ongoing research, this instrument will be an integral part of research and teaching at the undergraduate and graduate levels at Baylor University as well as Austin College, the University of Texas at Tyler and Texas Lutheran University.

The award is aimed at enhancing research and education at all levels, especially in areas such as (a) investigating biocoordination chemistry of HNO; (b) studying the mechanism of charge regulation in superoxide dismutase-1 and other metalloproteins; (c) studying the pro-oxidant chemistry of melanins; (d) designing, synthesizing and evaluating bioreductive tumor microenvironment; (e) analyzing radical reactions of trialkylborane water complexes; and (f) studying boron radicals, pyridyl phosphine/phosphine oxide coordination chemistry.

Microsystems, also known as Micro Electro Mechanical systems (MEMS), are becoming prevalent in daily life (e.g., wearable sensors, gaming consoles, sporting gear, smart phones, medical devices, and autonomous vehicles). This trend is driven by increasing functionality, decreasing device costs, and the Internet of Things (IoT) that need billions of sensors, actuators and communications devices. Given this increasing demand for microsystems, which has been growing at double-digits annually, there is both a jobs gap and a skills gap for such technologies, as well as STEM at large. The Southwest Center for Microsystems Education (SCME) will transition to a Support Center to work with community colleges and professional organizations to infuse microsystems educational materials into standardized job training and educational systems across several STEM disciplines. The STEM students benefit by being presented with alternative high technology microsystems career paths and having the knowledge to pursue them.

SCME has built a large portfolio of microsystems-based STEM educational materials and the supporting delivery infrastructure that have benefited hundreds of educators and thousands of their students. As a support center, SCME seeks to increase this impact several fold by providing asynchronous online and hands-on adaptable resources and the technical mentoring support needed for educational organizations to adopt and adapt SCME materials into their traditional STEM curricula. The SCME support center will provide a vehicle for partners to share their integration experiences and curricular modifications through conferences and online sharing opportunities. UNM will partner with the Lone Star College (LSC) system initially to pilot the introduction of microsystems into STEM courses. Historically, SCME has provided targeted professional development and microsystems courses to both Hispanic and Native American serving secondary and post-secondary institutions. SCME, with LSC and its Office of Diversity Initiatives, and student and industry professional associations, will provide scaled MEMS education, mentoring and career advisement targeted at underrepresented groups. This effort will inform SCME as it extends its reach using the standard of "Scaling Educational Innovations", and illustrates possible career pathways for technician students in the expanding microsystems arena.

PROJECT SUMMARY/ABSTRACT Over the past three decades, 28% of all new FDA approved drugs have been natural products, or derived from natural products, while 27% have been entirely synthetic in origin. Thus, the pursuit of new synthetic methods and strategies to access complex molecules is not only a worthy pursuit, but a critical component of biomedical research and drug development that also contributes novel elements of synthetic strategy and methods to the lexicon of synthetic chemistry. The studies proposed within this application describe the pursuit of six different natural products that fall into three general classes (diketopiperazine, alkaloid, and terpenoid). These compounds possess a range of biological activities including: leishmanicidal, NO production inhibition, anti- inflamatory, antiinsectan, antifungal, antiviral, cytotoxicity against a variety of cancer cell lines, as well as anti- proliferative activity. For the diketopiperazine and alkaloid projects we are aiming to develop ring expansion technology that will enable efficient access to imbedded hydroxamic acid intermediates. More specifically: Aim 1, entails syntheses of the N-hydroxy-2,5-diketopiperazine-derived (NHDKP) natural products haenamindole, raistrickindole A, and 14-hydroxyterezine D. This aim also includes the development of a regioselective ring expansion of tetramic acids that will enable the direct acces of to highly functionalized NHDKP?s. Aim 2 focuses on syntheses of phyllantidine and flueggeacosine B, two members of a securinega alkaloid subset that contain N-O bonds. The scope of the optimized ring-expansion chemistry developed in Aim-1 will be expand in this aim to deliver key intermediates in both syntheses. Aim 3 is a departure from aims 1 and 2 and turns toward further development of keteniminium chemistry by its application in a complex synthetic setting. At present, work toward each aim is at a different stage of development and this development will continue to evolve over the course of the grant period. As with all of our synthetic endeavors, collections of intermediates will be submitted to the NIH for SAR studies and once materials are in hand further collaborations are sought. In addition to direct contributions to biomedical science afforded by the latter, our synthetic efforts have (and will continue to) educate graduate students and postdoctoral researchers in the planning and execution of complex molecule synthesis.