Arthur D. Lander - US grants

This study concerns the role of proteoglycans in nervous system development. Proteoglycans, proteins that bear distinctive polysaccharides known as glycosaminoglycans, are widely distributed on cell surfaces and in the extracellular matrix. Many studies suggest that proteoglycans play critical roles in development, and this is thought to reflect their involvement in cell-cell and cell-matrix interactions. In the developing nervous system in particular, there is evidence that proteoglycans are involved in a variety of cell behaviors. Moreover, a striking proportion of proteins believed to influence neural development interact specifically with glycosaminoglycans. To understand the specific roles of proteoglycans in neural development, their sites and mechanisms of action must be defined. Before this can be done, however, it will first be necessary to identify the proteoglycans that are present in the developing nervous system and obtain tools that can be used to manipulate their functions. The expression of proteoglycans will therefore be examined in rat brain at various developmental stages (from embryonic to adult) and in various brain regions. Proteoglycans with provocative patterns of developmental and regional expression will be identified and monoclonal antibodies that recognize them will be obtained. Immunohistochemical data on the location and timing of expression of such proteoglycans will be used to suggest developmental events in which they participate. This information will then be correlated with two functionally important membrane protein?) and binding to glycosaminoglycan-binding proteins (does the proteoglycan bind selectively to proteins thought to mediate developmental events occuring when and where the proteoglycan is expressed?). The information and reagents to be obtained through this work are needed in order that direct in vitro and in vivo tests of the roles of individual proteoglycans in nervous system development may be conducted. Such studies will provide insights into the molecular mechanisms of mammalian brain development and will be directly relevant to the pathogenesis and treatment of development abnormalities.

The extracellular matrix protein laminin (LN) is thought to play a role in guiding visual system axons to their targets. During development, LN is localized along most of the routes followed by extend processes (neurites) in response to it. As development proceeds, retinal neurons lose the play a role in initiating the process of target innervation. Loss of response to LN might also contribute to the inability of retinal axons to regenerate following later injury. Although the above view of LN in the visual system is supported by many studies, a recent observation suggests unexpected complexity in the regulation of LN's effects on retinal neurons: If LN is treated with polyclonal antibodies specific to one of its protein domains (known as P1), it strongly promotes neurite regeneration by late embryonic retinal neurons. This is surprising because LN not treated with antibodies has no detectable effect on the same neurons (also, the antibodies do not themselves promote neurite growth). Interestingly, the receptor on late embryonic retinal neurons use to interact with untreated LN. Thus, retinal neurons have a receptor for LN that they do not use unless LN is somehow altered. Preliminary evidence suggest that anti-P1 antibodies bring about this alteration not simply by exposing a previously hidden site on the LN molecule, but possibly by altering the interaction between two activities located in different LN domains. Interestingly, an isoform of LN, known as merosin, possesses neurite regeneration activity for late embryonic retinal activities of LN and its isoforms can be regulated in previously unsuspected ways. Experiments are proposed to study how that regulation occurs. The receptor that late embryonic rat retinal neurons use to recognize anti-P1 tested LN will be identified. Three possible mechanisms by which anti-P1 antibodies activate a new function in LN will be tested. Studies will be carried out to determine the site on LN that anti-Pa antibodies recognize when they uncover new neurite outgrowth activity. These studies will lead to a better understanding of how molecules that control axon growth, such as LN, work. They are especially relevant to the visual system, because they suggest that growth and regeneration- promoting signals previously thought to be unavailable to retinal neurons may actually be available. Exploiting this fact could lead to new approaches for stimulating regeneration following retinal or brain injury.

neoplasm /cancer; biomedical facility; genetically modified animals; laboratory mouse; animal colony;

During nervous system development, growing axons navigate to their targets by responding to diverse cell-surface and secreted molecules. These "guidance molecules" act through multiple kinds of receptors to exert both stimulatory and inhibitory effects on axonal growth cones. The molecular mechanisms underlying these responses are poorly understood, yet insights into those mechanisms are likely to be of great importance in understanding and treating developmental disorders of the nervous system, as well as in improving the regenerative response to nerve, brain and spinal cord injury. Recently, we identified a protein, the B oligomer of pertussis toxin (PTb), that binds to chick primary sensory neurons and inhibits their responses to the guiding effects of three unrelated molecules--the extracellular matrix protein laminin (which can be patterned into pathways that growth cones closely follow), the secreted protein collapsin-1 (which repels growth cones and, under appropriate conditions, causes growth cone collapse), and the protease thrombin (which, acting through the thrombin receptor, causes growth cones to collapse and retract). Unlike intact pertussis toxin, PTb does not modify and inactivate G-proteins, rather, PTb acts by binding sialic acid- containing oligosaccharides on a subset of neuronal glycoproteins, and its effects on neurons can be mimicked by a sialic acid-binding plant lectin. It is unlikely that PTb acts by binding to and blocking the receptors for laminin, collapsin and thrombin, since PTb usually binds only a very small number of cell surface proteins with high affinity. In addition, PTb blocks only the guiding, and not the outgrowth-promoting effects of laminin. We hypothesize that PTb binds a cell surface receptor and modulates some signaling pathway in a way that specifically disrupts guidance by multiple classes of molecules. Elucidating such a signalling pathway could provide novel insights into how guidance molecules work and how their effects are integrated. We therefore propose to (1) investigate how PTb acts by testing specific hypotheses about the receptor mechanisms and signalling pathways involved in the inhibition of guidance responses by chick sensory neurons in tissue culture; (2) purify and identify the receptor through which PTb acts; and (3) look for direct associations of that receptor with known signaling pathways.

Cell surface heparan sulfate proteoglycans (HSPGs) are abundant, ubiquitous molecules, that bind via heparan sulfate (HS) chains to growth factors, extracellular matrix proteins, and other important cellular effectors. The major cell surface HSPGs are products of two gene families: the syndecans, which are transmembrane proteins, and the glypicans, which are glycosylphosphatidylinositol-anchored. Four syndecans and at least five glypicans are expressed in mammals, including man. The biological functions of cell surface HSPGs are poorly understood, but at least one function involves regulation of the responses of cells to polypeptide growth factors. Recently, a human birth defects syndrome associated with dysregulated tissue growth was shown to be caused by null mutations in glypican-3. Genetic studies in the fruitfly, Drosophila, have also linked loss of glypican function to defects in tissue growth and patterning. One tissue in which glypicans are likely to play especially important development roles is the nervous system. Experiments with cultured neutral cells and lower organisms have long pointed to crucial roles for HSPGs in neutral patterning, axon guidance, and synapse formation. Previous work on this project has demonstrated that glypicans-1 and -2 are among the most abundant HSPGs in the mammalian brain, and are expressed in locations such as neutral precursor zones, growing axons, and synaptic terminal fields, that are consistent with playing such developmental roles. The goals for the next project period focus on uncovering the functions of glypicans-1 and -2 in the mammalian nervous system, and on relating glypican function to structural features of the glypicans, such as the presence of HS chains, the mode of membrane anchorage, and presence of a large N- terminal globular domain that does not carry HS, yet has been highly conserved throughout evolution. Functional experiments involve the analysis of mice engineered to lack glypican-1, glypican-2, or both. Glypican-2 null mice have already been made, and the generation of glypican-1 null mice is in progress. Analysis of structure-function relationships in glypicans will use the fruitfly as an experimental system in which genes encoding altered glypicans can be rapidly and quantitatively tested for function. Finally, the results of observing mutant phenotypes and making structure/function correlations will be used to direct a genetic and biochemical search for the ligands with which glypicans interact in mammalian nervous system development. These studies should provide insights into how an important and poorly understood class of molecules regulates basic developmental processes, particularly in the nervous system.

The goals of this program is to identify and explore the mechanisms by which developmental signaling is regulated. The five component projects focus on one class of secreted molecules the TGF-beta-related bone morphogenetic proteins (BMPs) that play important roles in patterning both vertebrate and invertebrate embryos. Currently, there is a basic understanding of how BMPs, and their invertebrate homologues such as Drosophila decapentaplegic (dpp), interact with cellular receptors to produce a signal in the form of a phosphorylated cytosolic Smad protein that translocates to the cell nucleus and influences patterns of gene expression. How levels of BMP activity are controlled-spatially and temporally is much less well understood. Evidence exists of control mechanisms involving activation of gene expression; secreted BMP inhibitors; proteases that cleave BMP-inhibitors; proteins that interact with inhibitor-cleaving proteases; differential expression of receptor isoforms; expression of co-receptors; and the use of multiple Smads. Project I will investigate how the function of chordin, a BMP inhibitor whose levels control BMP function in the early Xenopus embryo, is regulated by the protease BMP-1 and other molecules. Project II will investigate the mechanism by which two BMPs in Drosophila, dpp and screw (scw) interact synergistically. Project III will investigate the mechanism of action of a potentially novel GPI-anchored cell surface protein that acts as a positive regulator of BMP-receptor binding in mammalian cells, as well as investigate the biological significance of BMP binding to heparan sulfate. Project IV will investigate why low doses of some BMPs promote the production of neurons in the mouse olfactory epithelium, while high doses inhibit neurogenesis; this project will focus bone on the mechanism of dose-dependent effects and on identifying the relevant BMPs and BMP actions in vivo. Project V will focus on the molecule twisted gastrulation (tsg), which is required for a dpp-dependent patterning event, but is structurally related to insulin-like growth factor binding proteins; this project will week to identify the interactions that und4erly the biological activities of tsg. Through collaborative and synergistic interactions among the projects, it is hoped that these studies will lead to a broader understanding of how developmental signaling pathways are regulated. Such pathways control virtually every aspect of cell behavior during development, and interference with these pathways is believed responsible for a large proportion of birth defects.

DESCRIPTION (provided by applicant): Scientists have long marveled at the complexity of biological systems. Although the presence of many components (genes, proteins, signaling molecules, cells) is an obvious way in which biological systems are complex, complexity also arises from the fact that biological components interact in interconnected, dynamic and, frequently non-linear ways. Whereas dealing with the first type of complexity often calls for the tools of statistics, database management, and automated analysis of large data sets, dealing with the second type of complexity calls more often for the tools of engineering, biophysics, and applied mathematics. A common interest in this second type of biological complexity has brought together an interdisciplinary group of 12 investigators at the University of California, Irvine, who are committed to working together to expand the scope of complex biological systems research on the campus. Many in the group have a common focus on transport and the interaction of transport processes with other cell- and tissue-level events. The group draws from departments in the schools of Biological Sciences, Medicine, Physical Sciences and Engineering, and possesses a synergistic combination of well-defined biological problems, state-of-the-art methods for detailed measurement of biological parameters, and first-class mathematical and computational capabilities for numerical solutions and simulations. This proposal seeks funding, in the form of a planning grant (P20), to support a three year period of expansion of research interactions and development of the necessary research, teaching and administrative infrastructure to become a Center of Excellence in Complex Biological Systems Research.

DESCRIPTION (provided by applicant): This application seeks partial support for the Tenth Gordon Conference on Proteoglycans scheduled for July 7-12, 2002, at Proctor Academy in Andover, New Hampshire. The previous conference was held July 9-14, 2000, at the same site. More than 200 applications were received, from which 153 registered participants were selected for a full capacity conference. All nine conferences to date have been over-subscribed. The 2000 conference was rated by attendees and Gordon Conference staff as "outstanding". The Gordon Conference on Proteoglycans is the main venue for presentation and discussion of current and future directions in the proteoglycan field, and consistently leads to new insights, new interactions, new collaborations, and new research directions. In planning the Tenth Conference on Proteoglycans, we will build on the successful tradition of previous conferences. The conference will take a broad approach to the structure, metabolism, molecular and biological functions, and pathology of this important class of macromolecules. This year the meeting will have a heavy emphasis on development, genetics and physiology in normal and abnormal situations. The scientific sessions will initially focus on novel developments in the proteoglycan field followed by talks on findings in the areas of, biosynthesis, metabolism, and structural biology. These topics will be followed by sessions on the roles of in the proteoglycans in cell biology, focusing on their participation in cellular signaling and their roles in the extracellular matrix. A subsequent session will focus on the specific roles of proteoglycans in development, with special emphasis on the use of genetic models and manipulation. Two subsequent sessions will emphasize the roles of proteoglycans in the cardiovascular, immune, nervous, and musculoskeletal systems, as well as their role in cancer biology. A final session entitled, "proteoglycans in the clinic" will specifically focus on proteoglycans in human diseases, both genetic and non-genetic. Because proteoglycans are important in a wide range of biological and pathological systems, this multi-disciplinary meeting targets a broad spectrum of investigators and is relevant to the mission of various NIH Institutes/Centers including those concerned with development and child health, musculoskeletal systems, inflammation and immunology, vision, cancer, heart and lung diseases, diabetes and kidney disease, and neurological disorders.

DESCRIPTION (provided by applicant): Positional cloning of rare multisystem genetic disorders that follow Mendelian inheritance patterns allows for the identification of genes and molecular pathways that play critical roles in human development. While the impact of disease gene identification on families affected by rare human disorders is tremendous, the true strength of these discoveries comes more from the insight they provide into the pathogenesis of more common and often isolated human structural developmental defects, the genes for which are much more difficult to map. Our recent discovery that mutations in NIPBL cause Cornelia de Lange syndrome (CdLS), a dominantly inherited genetic developmental disorder, provides a starting point to identify downstream genetic targets that are involved in the multiple structural and developmental defects that accompany this diagnosis (craniofacial, limb, gastrointestinal, cardiac, genitourinary and others). The function of NIPBL in mammals is largely unknown, however work in Drosophila has shown that its homolog Nipped B regulates the cohesin complex, and through this function controls long range enhancer-promoter interactions. This program project builds on the strengths, experience and resources available to the project leaders, all of whom have been actively involved in a fruitful collaboration since the identification of NIPBL as the CdLS disease gene. The PI and project leaders will work together to sytematically study NIPBL, its interacting proteins and downstream target genes and to characterize the effects this gene and pathway has on human structural birth defects. A three-pronged approach to studying this gene and pathway in humans (Project I), mouse and zebrafish (Project II) and Drosophila (Project III) will synergistically characterize the function, interactions and role of NIPBL and its downstream targets in causing syndromic and isolated human structural birth defects. This project will be supported by a data- and resource-sharing core that will fuel all three projects and an adminsitrative core to oversee and facilitate and optimize the interactions of all projects. Lay Language: Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder caused by mutations in NIPBL, a novel gene involved in regulating downstream genes through long-range enhancerpromoter interactions. This proposal outlines a plan to characterize NIPBL's function, identify its target genes and evaluate their role in causing isolated structural birth defects of the types seen in CdLS.

Systems biology seeks to understand relationships between the design of biological systems and the complex tasks they have been molded, by natural selection, to perform. In biological systems, events happen not only in time, but also in the realm of space: Cells and organisms recognize spatial information (e.g. chemotactic gradients, visual patterns), generate spatial information (body patterns, tissue architectures), and may even use spatial information as a computational tool. The focus of the proposed center is on how spatial information is handled by biological systems, and how it ultimately is used to create biological form (morphogenesis). The center will support a program of interdisciplinary research, technology development, training, and outreach aimed at furthering the development of the spatial side of systems biology. The research projects are organized into three themes, focusing on pattern formation during development, the control of proliferative dynamics in epithelia, and spatial aspects of the regulation of intracellular signaling. Projects within these themes will take advantage of a variety of approaches (genetics, biochemistry, biophysics, mathematical modeling, computation) and experimental organisms (yeast, flies, zebrafish, frogs, and mice). Technology development will focus on mathematical/computational tools and optical biology tools that address some of the unique challenges associated with measuring and modeling spatially dynamic systems. Training will include programs at the undergraduate, graduate and postgraduate levels for educating the next generation of systems biologists. The goals of the program will be met through the collaborative efforts of twenty faculty at U.C. Irvine, representing a mix of biologists, mathematicians, physicists, engineers and computer scientists. Among other things, the efforts of the center are expected to identify common principles in how different kinds of biological systems manage the spatial world. Such insights will have a broad impact on a variety of health-related areas including human development and birth defects, stem cells and regeneration, normal and tumor cell growth, and basic physiology.

CRISP; California; Computer Retrieval of Information on Scientific Projects Database; Educational workshop; Fluorescence; Fluorescence Microscopy; Funding; Grant; Image Analyses; Image Analysis; Institution; Investigators; Laboratories; Lectures; Lectures (PT); Lectures [Publication Type]; Length; Microscopy; Microscopy, Fluorescence; Microscopy, Light, Fluorescence; NIH; National Institutes of Health; National Institutes of Health (U.S.); Programs (PT); Programs [Publication Type]; ROC Analysis; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Spectroscopy; Spectrum Analyses; Spectrum Analysis; United States National Institutes of Health; Universities; Workshop; day; image evaluation; lectures; programs; tool; training project

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Theme A: Specification of Macroscopic Pattern Theme Leader: Lander. Other Project Faculty: Marsh, Nie, Schilling, Wan, Warrior, Xin, Yu Much of the macroscopic patterning of tissues is orchestrated by gradients of extracellular signaling molecules known as morphogens, which act during embryonic stages over distances of many tens of micrometers, to influence cell fates in a spatiallydependent manner. Morphogen gradients position boundaries of gene expression that define the locations of germ layers, body segments, and many tissue elements. In recent years, much has been learned about the identities of morphogens, and the receptors and signaling pathways used by cells to detect them (Neumann and Cohen, 1997;Tickle, 1999;Green, 2002;Tabata and Takei, 2004;Ashe and Briscoe, 2006). Morphogen gradients have long intrigued mathematicians and physicists because the problem of creating complex forms de novo (or from simpler forms) is mathematically interesting, and has general applicability to both physical and biological systems. Indeed, mathematicians (such as Turing, and Gierer) and engineers (Wolpert) developed a whole field of theoretical morphogen gradient study (Murray, 1993) long before biologists were willing to agree that morphogens even exist. As the study of morphogen gradients has increasingly moved into the hands of experimentalists, it has emerged that most morphogen gradient systems are far more complex than had been expected. Signs of complex control circuitry[unreadable]feedback loops, secreted inhibitors, coreceptors, regulation of diffusivity, cooperative interactions among morphogens[unreadable]abound, implying that morphogen gradients are constructed to do far more complex things than theoreticians had anticipated (Lander, 2007). What are the "missing" performance objectives of morphogen gradients? This question has come to dominate much of the experimental and theoretical work in the field. Some investigators have focused on questions of morphogen transport: Is simple diffusion adequate to create useful gradients? Does experimental evidence support the existence of active transport mechanisms that supplement or replace diffusion? Why are some morphogens covalently modified with cholesterol or fatty acids, which should make them less diffusible? Other investigators have focused on questions of robustness, i.e. the insensitivity of patterning to genetic or environmental perturbation. This is a rich area for investigation because experiments show that many patterning systems are extraordinarily robust, far more so than predicted by "classical" morphogen models. A recent assessment suggests that the performance objectives of morphpogen gradient systems go even deeper than just providing for insensitivity to environmental and genetic change (Lander, 2007). Some such systems appear to be under difficult time constraints;others may need to suppress internal noise (see below);in some cases different classes of morphogens may work together to overcome each other's inherent limitations (White et al., 2006). Clearly there is a great deal to be learned about what morphogen gradient systems are doing, and what strategies they exploit to do it. This area provides especially fertile ground for model exploration, and several good examples of large-scale parameter space exploration have come from this field (e.g. von Dassow et al., 2000;Eldar et al., 2002;Eldar et al., 2003;Ingolia, 2004). Efforts have also progressed toward building detailed mechanistic models for validation (Goentoro et al., 2006;Reeves et al., 2006), although it is clear that barriers to measuring key parameters such as levels of morphogens and receptors, and rate constants of production, interaction and destruction, need to be reduced.

ALK-3 receptor; Abscission; Apoptosis; Apoptosis Pathway; BMP type IA receptor; BMP-2; BMP-2A; BMP2; BMP2 gene; BMP2A Gene; BMPR-IA; BMPR-II; BMPR1A; BMPR2; BRK-3 protein; Biochemical; Bone Morphogenetic Protein 2 Gene; Bone Morphogenetic Protein 2A Gene; Bone Morphogenetic Protein Receptor, Type II (Serine/Threonine Kinase); Bone Morphogenetic Proteins; CRISP; Cell Communication and Signaling; Cell Death, Programmed; Cell Signaling; Cell surface; Cell-Extracellular Matrix; Chondrogenesis; Class; Computer Retrieval of Information on Scientific Projects Database; Confocal Microscopy; Data; Developmental Process; Dimerization; Dorsal; ECM; Excision; Extirpation; Extracellular Matrix; Fluorescence; Funding; GFAC; Glycans; Glypican; Grant; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; HSPG; Heparan Sulfate Proteoglycan; Inorganic Sulfates; Institution; Intracellular Communication and Signaling; Investigation; Investigators; Ligands; Mammalian Cell; Mammals, Mice; Mice; Microscopy, Confocal; Modification; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neural Growth; Neuronal Growth; PC-12; PC12 Cells; Pattern; Pheochromocytoma Cell Line; Polysaccharides; Procedures; Protein Dimerization; Proteins; Proteoheparan Sulfate; Receptor Protein; Removal; Research; Research Personnel; Research Resources; Researchers; Resources; Role; Signal Transduction; Signal Transduction Systems; Signaling; Source; Sulfates; Sulfates, Inorganic; Sulfates, Unspecified or Sulfate Ion; Surgical Removal; Testing; Time; Title; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; activin receptor-like kinase 3; biological signal transduction; bone morphogenetic protein 2; bone morphogenetic protein receptor II; bone morphogenetic protein receptor type II; bone morphogenetic protein receptor, type IA; bone morphogenetic protein receptors; gene product; insight; neurogenesis; pheochromocytoma 12 cell line; polypeptide; receptor; receptor, BMP; receptor, type II BMP; resection; social role; sulfate; type IA bone morphogenetic protein receptor

Attention; CRISP; Computer Retrieval of Information on Scientific Projects Database; Funding; Grant; Institution; Instrumentation, Other; Investigators; Methods and Techniques; Methods, Other; NIH; National Institutes of Health; National Institutes of Health (U.S.); Programs (PT); Programs [Publication Type]; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Students; Systems Biology; Techniques; United States National Institutes of Health; instrumentation; programs

DESCRIPTION (provided by applicant): Biology is in the midst of intellectual upheaval. An era dominated by the systematic identification and characterization of parts-genes, proteins, cells-is rapidly yielding to one focused on complex interaction networks, the principles of their design, and their role in the context of organismal fitness and natural selection. The emerging field of Systems Biology breaks with the past not only in the types of questions it asks, but also in the diverse disciplines it draws heavily upon, including mathematics, computer science, engineering, and physics. Here we outline Phase II in the development of a training program in Mathematical, Computational and Systems Biology that was initiated under Phase I of the Howard Hughes Medical Institute/NIBIB "Interfaces" initiative. The program is a coordinated, interdisciplinary program designed to produce Ph.D.s that are prepared for careers in Systems Biology. Highlights of the program include an extensive didactic curriculum;a focus on critical thinking skills;an emphasis on collaboration and collaborative learning;close mentoring, opportunities to develop career skills;and active student involvement. The 38 program faculty members come from eleven different departments and five schools at the University of California, Irvine, and conduct research on diverse topics within Systems Biology. The program enjoys strong campus support and an administrative and intellectual home within an NIH-supported National Center for Systems Biology at UCI. RELEVANCE: Biological and biomedical research are increasingly focused on complex systems. By training the next generation of researchers in an interdisciplinary mode-blending biology with mathematics, computer science, engineering and physics, the proposed program will help future scientists and educators function effectively in this new research environment.

The mission of the Transgenic Mouse Facility at UC-lrvine is to facilitate the use of genetically modified mice in hypothesis-driven research by providing services for making, breeding, genotyping, importing, and preserving mouse strains. Our primary goal is to offer these services at the lowest possible cost while producing yields and outcomes that compare favorably with similar facilities at other academic institutions. We are in a strong position to assist in the development of in vivo mammalian models of cancer and to provide strains of mice that are critical to understanding the molecular basis of cancer.

DESCRIPTION (provided by applicant): Embryonic development is a spectacular feat of engineering, wherein complex networks of tens of thousands of components are harnessed to achieve growth, differentiation, and patterning that is amazingly robust to intrinsic variability and extrinsic perturbation. Systems Biology is an emerging, hybrid discipline - incorporating elements of mathematics, computer science, and engineering - which seeks to analyze complex biological networks and elucidate the design principles that underlie robust performance. Systems Biology holds great promise for addressing fundamental questions in developmental biology, but progress has been hindered by a paucity of individuals with adequate training in both experimental developmental biology and the mathematical and computational disciplines. A predoctoral training program is proposed to remedy this situation. Advanced students at the University of California, Irvine who have already committed to thesis work in Developmental Biology or Systems Biology will receive cross-training through classes, dual mentoring, presentations and career development activities. Trainees may come from any of the nine departmental Ph.D. programs to which 26 faculty trainers belong, including Developmental and Cell Biology, Anatomy and Neurobiology, Biological Chemistry, Neurobiology and Behavior, Mathematics, Computer Science, Physics and Biomedical Engineering. This program will leverage diverse educational resources that are present at University of California, Irvine as a result of its history of strength in Developmental Biology and its recent NIH designation as a National Center for Systems Biology. RELEVANCE: Embryonic development is orchestrated by massive networks of gene regulation and signaling. To understand how and why birth defects arise, it is essential to understand these networks as complex systems, with design strengths and weaknesses. By studying the Systems Biology of Development, trainees will prepare for cutting edge research into the causes and treatments of birth defects.

DESCRIPTION (provided by applicant): Cancer is a disorder of unrestrained cell proliferation, but increasingly it seems that not all proliferating cells in a tumor matter equally. As with cells in normal tissues, tumor cells appear to progress through lineage stages, in which the capacity for unlimited self-renewal is, at some point, lost. The cancer stem cell hypothesis states that cancer diagnostic, prognostic and therapeutic efforts need to be focused on that population of cells-often a small minority-that undergoes long-term self-renewal. While this hypothesis acknowledges the existence of lineage progression in cancers, it is silent on the function that lineages normally serve. We recently found, through experimental and theoretical work, that a likely raison-d'etre for lineages is to provide a framework for powerful feedback control of growth and regeneration, through mechanisms that target the differentiation decisions of individual cells. For cancer to develop, such feedback control must be disrupted, and the natural history of most tumors suggests that it becomes disrupted progressively over time. Our studies indicate that what happens in a tissue when feedback is compromised can be very complex, yet still understandable and predictable. We argue, therefore, that from the details of how a tumor develops over time-size, shape, growth rate, stem cell fraction, etc.-one ought to be able to infer specific information about the kinds of control processes that operate (or recently operated) within the tumor and its surrounding environment. Such information can both provide insight into how different types of tumors develop, as well as patient-specific information about prognosis and the effects of therapy. The proposed project focuses on learning how to obtain such information from the observable properties of tumors. Three-dimensional mathematical models that incorporate various types of lineage progression, feedback, evolutionary processes, and therapeutic interventions will first be created, analyzed, and used to generate large numbers of simulations of solid tumor growth and progression. From these results, mappings from tumor properties to feedback and lineage architectures will be found through state-of-the art machine-learning algorithms. The ability of these mappings to reproduce and predict the behaviors of real tumors will be assessed using established animal models of breast cancer, in which luminescent and fluorescent imaging techniques are used to follow tumors, and their stem cells, over time. This will enable the validation of particular model architectures, or suggest methods for their refinement, and allow the determination of control strategies at work in tumors that can be exploited to provide a leap forward in both personalized medicine and cancer care. What makes this project a "grand opportunity" is the pursuit of rapid progress through a highly multidisciplinary team that will draw on new advances in the areas of cell lineage behaviors, cancer stem cells, three-dimensional mathematical and computational modeling, and machine-learning. PUBLIC HEALTH RELEVANCE: Tumors arise when the feedback control of cell growth breaks down. We hypothesize that, within the details of how a tumor grows lie important clues about the nature of feedback processes-including those that still remain or may be re-activated. By describing how such clues can be found, we will be defining a new approach for predicting how individual tumors behave in cancer patients, and how they respond to different kinds of therapy.

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. Preparation and use of microscopes to test and prepare a brief laboratory course for incoming graduate students of the MCSB program. Many of the new students have backgrounds in the Physical Sciences and need a review of Biology. Lectures in Biological Computations and general lectures in areas of Biology will be given over a three week "Boot Camp". In addition, several laboratory segments are being designed to complement the lectures and for which microscopes of the LFD will be used. Work is ongoing.

DESCRIPTION (provided by applicant): This proposal aims to establish a National Short Course in Systems Biology that integrates mathematical, statistical and computational approaches to describe biological systems and understand their complex behaviors. The Center for Complex Biological Systems (CCBS) at UC Irvine is ideally suited to host this annual course being one of ten NIH National Centers for Systems Biology. The CCBS is able to leverage substantial faculty educational and research expertise - from a pool of more than 100 active faculty from 18 participating science departments, as well as contributions from preeminent resource facilities such as the Laboratory of Fluorescence Dynamics (LFD) and the Institute for Genomics and Bioinformatics - to create a top-rated training course designed for senior graduate students, postdoctoral researchers, faculty and industry scientists from diverse scientific disciplines who have nascent interests in engaging in Systems Biology research. The course theme will focus on the systems biology of spatial dynamics that impacts key cellular processes including signal transduction networks, cell differentiation, and developmental mechanisms of morphogenesis and patterning. Moreover, experience gained in these systems will enable trainees to apply these skills more generally to other complex systems with spatially dynamic properties. Recruitment and training of research scientists in this thematic area is currently underserved but demand is expected to be significant given the central importance of these processes to many human health related issues, including developmental abnormalities, age-related disease processes, initiation and progression of cancer and infectious disease models that are amenable to systems-oriented analysis and dependent on spatio-temporal factors. The course format will combine didactic lectures with hands-on practical laboratories featuring both biological experimentation and mathematical/computational modeling tutorials. The course design is organized into two principal sections: an optional 1-week Introductory Preparatory Workshop (either in Biology or Mathematical/ Computational Methods) will address individual trainee educational weaknesses by providing essential cross-disciplinary foundational instruction. The second part consists of a 2-week Systems Biology Core Course offering a high-level introduction to spatially dynamic research topics and advanced analytical biometric tools (e.g. advanced correlation spectroscopy and pipeline queries to bioinformatic databases) through project oriented instruction and small group interactions. This unique approach of addressing specific trainee educational deficiencies first, then building strong interdisciplinary collaborative work groups, will enhance course recruitment and entry into this field to research scientists who frequently feel interested but intimidated due to a perceived lack of prior formal training. Beyond providing an intensive on-site training course, all lecture materials (video recorded), training datasets, and software tools will be made freely available through on-line distribution to maximize our outreach efforts.

DESCRIPTION (provided by applicant): Morphogen gradients are widely used to provide cells with the positional information needed to create spatial patterns of gene expression. Such pattern formation underlies a great deal of developmental morphogenesis, and is notable for its accuracy and reproducibility. Indeed, a large fraction of human birth defects are the direct result of relatively small disruptions in pattern formation. In most cases, the formation of morphogen gradients, and the responses of cells to them, is subject to complex regulation by networks of interacting transcription factors, receptors, and co-receptors. It is likely that such regulation evolved to make spatial patterning robust to biologically relevant perturbations (genetic variability, environmental uncertainty, intrinsic stochasticity, etc.). Focusing on the BMP gradient that patterns the antero-posterior axis of the Drosophila wing imaginal disc, we will explore and elucidate the mechanistic basis for robust patterning, through a collaborative approach that closely intertwines experimental biology with mathematical modeling and analysis. Three related areas of investigation will be pursued: First, we will quantify the cell-to-cell variability that normally impedes the ability of tissues to generate sharp borders of gene expression in response to shallow morphogen gradients, and investigate how such spatial noise changes at different stages within the gene regulatory network that controls wing vein patterning. Second, we will pursue recent evidence suggesting that patterning is sensitive not only to levels of morphogen in a gradient but to the local gradient slope as well. As part of this work we will test the hypothesis that slope detection is mediated by the Fat signaling pathway, and serves the purpose of reducing spatial noise. Third, we will extend previous mathematical models of morphogen gradient formation and interpretation in order to elucidate the tradeoffs that arise among regulatory mechanisms that serve as strategies for achieving robustness with respect to individual types of perturbations. In particular, such models will incorporate mechanisms and performance objectives that have not heretofore been analyzed mathematically. Broadly, the goal of this work is to provide a more coherent understanding of how complex regulation of spatially dynamic biological systems is utilized to achieve robust performance under a wide variety of conditions. Ultimately, the results should provide insights into the pathological processes that lead to structural birth defects and other developmental abnormalities. )

THEME A - CONTROL OF PATTERN (Arthur Lander, Theme Leader) I Understanding pattern - the regular arrangement of cells and cellular behaviors in space - is one of the oldest problems in biology. Over the past half-century, two views of pattern formation have flourished [63,64], both appealing to the actions of molecules, termed morphogens, that spread within tissues. In boundary-organized' patterning, long-range morphogen gradients provide positional Information, giving cells their coordinates with respect to a frame of reference. In self-organizing patterning, morphogens act over shorter range to induce or repress expression of themselves or other morphogens, which in turn influences their own activity. Such feedback creates instabilities that lead to spontaneous division of cell groups into repeating units. Aim A l , below, explores changing concepts in how long-range morphogens control pattern. Aim A2 pursues the idea that patterning is often neither boundary- nor self-organized, but a combination of both. A third aim explores how pattern control and growth control are coordinated (it is designated Aim ABS, to reflect the fact that it will be a joint effort between Theme A [pattern] and Theme B [growth control]).

Systems Biology;

Systems Biology seeks to explain the complexity of life by revealing the basic strategies used by organisms to carry out diverse, demanding tasks in an uncertain world. Many Systems Biological approaches focus on the dynamic nature of living systems, but cells, tissues, and organisms don't just vary in time, they vary in space. Patterns must be specified, shapes and sizes must be controlled, and transport of signals and cargoes from one location to another must be regulated. For the last 4-1/2 years, the Center for Complex Biological Systems at the University of California, Irvine has operated as a National Center for Systems Biology, with a focus on Spatial Dynamics, the study of spatial phenomena and spatial design principles in biology. Taking advantage of collective strength in modeling, imaging and experimental methods, teams of molecular and cellular biologists, mathematicians, computer scientists, physicists and engineers have worked together to tackle a variety of spatial problems, from the subcellular to the organ level. During the next five years, the center proposes to extend this work with new research in five theme areas: pattern formation; tissue growth control; spatial control of intracellular signaling; development of mathematical and computational tools; and developmental of optical tools for spatial dynamics and nano-imaging. In addition, the center will maintain and expand upon an array of educational and outreach activities developed during the current funding period, including graduate, undergraduate and high school training activities; a short course for professionals in Systems Biology; faculty recruiting; symposia, workshops, regional meetings, retreats, and activities aimed at promoting workforce diversity.

This Integrative Graduate Education and Research Traineeship (IGERT) award initiates a novel model for interdisciplinary graduate training in biophotonics across the biomedical sciences, physical sciences, and engineering. Biophotonics technologies provide powerful capabilities to probe and manipulate biological components and processes. Their utilization in the life sciences and medicine represents an estimated annual economic impact of $50 billion. This program aims to produce the next generation of biophotonics leaders to make transformative advances in the development and application of new tools for biological and medical discovery and maintain global U.S. leadership in biotechnology, pharmaceutical and medical device industries.
Intellectual Merit: This IGERT award creates a hands-on training program that integrates physics, chemistry, engineering, and life-science principles across spatial and temporal scales. The interaction of, and collaboration between, biomedical scientists, physical scientists and engineers throughout the graduate traineeship will drive advances in biophotonics technologies, computational methods, and molecular probes to solve important problems in bio-molecular, cellular, tissue, and whole organismal systems.
Broader Impacts: The BEST IGERT project will promote dissemination of an innovative education framework aimed towards a diverse cadre of scientists and engineers. Moreover, IGERT faculty and trainees will engage vigorously in a spectrum of outreach, dissemination, recruitment, retention, and career development activities that leverages the commitment of multiple units within UC-Irvine, industry in Southern California, and a nationwide network of faculty contacts, including those at minority serving institutions, to inform the public and broaden participation by students from underrepresented groups.

IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to establish new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries, and to engage students in understanding the processes by which research is translated to innovations for societal benefit.

Cornelia de Lange Syndrome (CdLS) is a multi-organ system constellation of birth defects caused by dysfunction of cohesin, a protein complex required for chromosome cohesion, and recently implicated in the regulation of gene expression. This work will continue the development and analysis of two animal models of A//pib/-deficiency, the most common genetic cause of CdLS. The Nipbl+I- mouse replicates many features of CdLS including a high frequency of cardiac septal abnormalities. The A//pW-morphant zebrafish also displays cardiac defects, as well as gut defects that are typical of CdLS. In both systems, Nipbl deficiency appears to cause hundreds of relatively small, often tissue-specific, changes in gene expression, just as has been seen in cell lines from individuals with CdLS. The goal of the proposed work is to exploit the mouse and fish models to (1) understand the origins of heart defects in CdLS, and (2) determine the extent to which major structural defects in CdLS have a combinatorial etiology-i.e. arise as the result of synergistic interactions among small changes in the expression of multiple genes. The first aim will be accomplished using newly-developed transgenic mouse lines that harbor conditional/invertible (FLEx) alleles of Nipbl, which may be successively toggled from functionally-mutant to wildtype, and back again to mutant. Using these mouse lines, the timing and cell type(s) of origin of cardiac septal defects will be pinpointed, and potentially causal changes in gene expression identified. The second aim will be accomplished using a zebrafish model of CdLS. Experiments in this aim will focus on the identification of new potential Nipbl target genes, and the quantitative manipulation of their expression during early embryogenesis. Accomplishing these aims should not only aid in understanding, treating and/or preventing birth defects in CdLS; it is also likely to provide novel insights into the origins of non-syndromic birth defects, which are much more common, but may also frequently result from combinatorial interactions among small-effect alleles in the general population. RELEVANCE (See instructions): The impact of structural birth defects on human health is enormous. Animal models of Cornelia de Lange Syndrome (CdLS) will be exploited to generate new insights into the origins of birth defects, especially those of the heart and gut. Because of the way the gene defect underlying this syndrome works, there is a good probability that the results obtained will be directly relevant to common causes of birth defects in the general population.

DESCRIPTION (provided by applicant): The long term goal of this Program is to elucidate the manner in which disruption of normal cohesin function results in the multisystem developmental disorder Cornelia de Lange syndrome (CdLS) and to identify downstream effectors of cohesin function that are important in the pathogenesis of more common isolated birth defects of the types (e.g. congenital heart defects, cleft palate, diaphragmatic hernias, limb defects) seen in constellation in CdLS. The PI (Dr. Krantz) and Project Leaders (Dr. Lander and Dr. Dorsett) of this Program established a successful collaboration since the Pi's discovery of the first CdLS gene (NIPBL) and the initial implication of cohesin in human developmental disorders. At the inception of this Program the role of NIPBL and cohesin in mammalian development was largely unknown. Dr. Dorsett's discovery that the NIPBL ortholog in Drosophila (nipped-b) was a key regulator of gene expression, prompted the initial hypothesis that disruption of cohesin's non-canonical role in gene regulation was the underlying mechanism involved in causing CdLS. This Program Project has built, and will continue to build, on the diverse, but complementary, strengths, experience and resources available to the project leaders. A three-pronged approach to studying this gene and pathway in humans (Project I), mouse and zebrafish (Project II) and Drosophila (Project III) has led to significant discoveries into how cohesin and its regulators function, the identification of novel CdLS genes, the characterization of a group of developmental disorders collectively termed cohesinopathies, as well as the establishment of valuable resources including the only Nipbl mutant mouse model, multiple mutant Drosophila lines and the world's largest repository of cohesin mutant human cell lines and clinical information. In this renewal our collaborative team will use innovative approaches to continue to synergistically characterize the function, interactions and role of the structural and regulatory cohesin proteins involved in CdLS, and their downstream targets, in causing syndromic and isolated human structural birth defects. This Program is supported by a data- and resource-sharing core that will fuel all three Projects and an administrative core to oversee, facilitate and optimize the interactions of all Projects. RELEVANCE: CdLS is a multisystem developmental disorder caused by mutations in structural and regulatory cohesin genes. Recent discoveries have identified a non-canonical role of cohesin as a critical regulator of gene expression, disruption of which results in significant developmental consequences. This Program outlines a plan to characterize cohesin's function in gene regulation, identify its effector genes and evaluate their role in causing isolated birth defects of the types seen in CdLS.

? DESCRIPTION: The sizes of tissues and organs are specified with great precision, a fact we notice in the symmetry of bilateral structures (such as limbs), and the degree to which genetically identical individuals resemble each other. Not only do tissues and organs reach specific sizes, they do so in the face of cell killing or alterations to cell cycle kinetics, which suggests a feedback control mechanism. Work from our group on continually- renewing tissues has identified a general integral negative feedback strategy, whereby negative regulation of stem or progenitor cell renewal automatically achieves robust set-point control. Such feedback may be conveyed by diffusible growth factors-as we and others showed in the olfactory epithelium (OE), retina, and muscle-but a variety of molecules and mechanisms could act similarly. Regardless of mechanism, however, the ability of local feedback to control proliferation is subject to distance limitations: molecular and mechanical signals decay over characteristic length scales. The fact that such scales are often very short-on the order of 100 µm or less-raises questions about how local feedback could possibly control the sizes of tissues and organs that are three or four orders of magnitude larger. Here we address this issue through a combination of mathematical modeling and animal experimentation. Preliminary modeling has identified several strategies that could, in principle, enable large sizes to be controlled through short-range feedback. These strategies exploit the fact that controlling developmental tissue and organ growth is not a steady-state problem, but one of controlling a self-terminating trajectory. By considering a variety of possible cell lineage relationships and types of feedback interactions-all of which are motivated by observations in actual developing systems-we will use modeling and simulation to systematically discover the design principles out of which strategies for feedback control of large tissues and organs may be constructed. Subsequently, we will computationally test the hypothesis that the best way to distinguish experimentally among different potential growth-control strategies is by transiently ablating defined proportions of cells at specific lineage stages, and observing the consequences for final tissue size. Finally, we will perform just such transient cell ablations to investigate the development of three neural structures-the olfactory epithelium, the neural retina, and the cerebral neocortex-in mice, with the goal of identifying the strategies these tissues use for size control in different dimensions. This work will provide both basic insights into fundamental processes of development, and specific insights into size control in the nervous system. The results will be of direct relevance o the etiology of microcephaly and other birth defects, as well as to clinical phenomena of stunting, catch-up growth, and growth-asymmetry.

We propose a program to enhance the training and career development of scientists who seek to undertake interdisciplinary biological and biomedical research that draws upon ideas and tools from mathematics, physics, engineering and computer science, as embodied by the young field of Systems Biology. The program is centered upon a three-week intensive course at UC Irvine, followed by one to two years of follow-up mentoring and career development activity. The course is intended for graduate students, postdocs and more advanced scientists, both those with backgrounds in experimental biology?who typically need additional preparation in mathematics and computation?and those with backgrounds in mathematics, physics, engineering or computer science?who usually need additional preparation in the foundations of biology. We aim to train around 20 individuals each year. The proposed program begins with a one-week preparatory workshop, followed by a two-week core course in which lectures and laboratory modules will expose participants to cutting-edge interdisciplinary methodologies and research topics. The program will also feature extensive mentoring and career-skill building activities, including panel discussions, presentations, mentored team projects, and individually-guided development of research or fellowship proposals. These activities will involve 27 UCI faculty with research and teaching expertise in mathematics, physics, computer science, engineering and the biological sciences. Outreach activities include dissemination of information through online resources and a systems biology regional conference, as well as participation in workshops at interdisciplinary and minority conferences. The specific goals of the course include (i) conveying an understanding of Systems Biology and its interdisciplinary nature; (ii) filling gaps in technical expertise and vocabulary, and developing a deep understanding of mathematical models; (iii) acquainting participants with the challenges of collaboration and communication in interdisciplinary research, (iv) fostering community building, and (v) enhancing career development. Lecture materials (video-recorded), training datasets, and software tools will be made freely available through on-line distribution to maximize outreach. Course administration and logistics will be handled by the UC Irvine Center for Complex Biological Systems (CCBS), an NIH-designated National Center for Systems Biology.

PROJECT SUMMARY Congenital heart disease (CHD) is genetically complex, with most cases likely reflecting combined effects of variation at multiple genes. Current methods, both statistical and experimental, for discovering causal alleles of genes that produce disease phenotypes only in combination, are very limited. These limitations are a major reason why the genetic origins of most CHD remain unknown, and there is a pressing need to overcome them. To address this need, we propose a novel approach, which exploits genetic syndromes known as ?transcriptomopathies,? in which transcription is globally, yet subtly, disrupted. In one of these, Cornelia de Lange Syndrome (CdLS), small changes (mostly <1.5-fold) occur in transcript levels for up to 1,000 genes in each cell. This results in a reproducible spectrum of birth defects that includes CHD. CdLS is most commonly caused by haploinsufficiency for NIPBL, a gene that encodes a cohesin-regulatory protein, and mouse and zebrafish models of Nipbl-haploinsufficiency replicate CdLS phenotypes. Such animal models provide a means to identify how sets of perturbations to gene expression which do not individually cause disease, can act collectively to produce heart defects?thus modeling the multi-genic causation of CHD. Our investigation of such models suggests that causal events likely occur early in embryogenesis during the initial morphogenesis of the heart. Recently, using mouse models in which Nipbl-haploinsufficiency can be switched on and off in different embryonic cell lineages, we discovered that risk for atrial septal defects (ASDs), the main form of CHD in Nipbl+/- mice, is controlled by non-additive interactions between gene expression changes in cardiomyocytes and their progenitors; cells derived from endoderm, endocardium or endothelium; and cells of the rest of the embryo. We now propose to exploit the genetic manipulability of this system to identify both the morphogenetic abnormalities and the individual gene expression changes that collectively produce ASDs. By analyzing early morphogenesis in globally- and conditionally-mutant embryos we will test several hypotheses concerning the role of progenitor cell proliferation, patterning and migration, with a particular focus on the progenitors of the second heart field, which preliminary results suggest may be central to ASD causation. By using a variety of Cre recombinase-expressing mice to conditionally create, and rescue, Nipbl- haploinsufficiency in a variety of lineages, we will investigate the roles of distinct subpopulations of cells in both increasing and decreasing ASD risk. Finally, we will use single-cell RNA sequencing of early embryos to identify gene expression changes associated with Nipbl-haploinsufficiency in those cells responsible for causing ASDs. The result of these studies will be to develop novel, directly testable hypotheses about mechanisms that underlie multifactorial, and multi-genic, CHD.

The proposed Center for Cancer Systems Biology, to be known as the Center for Complexity, Cooperation and Community in Cancer, is a joint effort by the systems biology and cancer biology communities at the University of California Irvine (UCI), as represented by two campus-wide research organizations, the Center for Complex Biological Systems and the UCI Cancer Research Institute. The center will tackle a variety of basic and fundamental questions about cancer systems, and why they are organized as they are. The premise underlying the research program of the center is that cancer cells proliferate and evolve in complex environments that have been highly selected for the robust control of growth and differentiation, and that the behaviors of cancer cells can only be fully understood in the context of the design principles that govern that control. As described in this proposal, the center will carry out three coordinated, team-oriented research projects on the role of context, cooperation and community in the initiation and progression of cancer. One project will leverage new observations from xenograft models of colon cancer to investigate non-genetic heterogeneity in solid tumors, both its origins and its relevance to tumor growth and response to therapy. A second project will investigate the cellular origins of melanoma, seeking to clarify the relationship between melanoma and the benign lesions (melanocytic nevi) that are driven by a common oncogenic event. This work will focus on interactions among melanocyte precursors, within the skin environment, and under conditions that promote progression from benign to malignant. The third project will focus on improving models of chronic myeloid leukemia (CML) and its treatment, taking into account interactions between hierarchical lineages, intercellular feedback, and dynamics. All three projects will combine mathematical modeling, genomics, and experimental manipulation of animal models. All three will be served by a core facility for investigating tumor cells at the single cell level, providing access to the latest in single-cell genomic, transcriptomic and other technologies. The center will also support short-term, interdisciplinary pilot projects initiated both by faculty and by trainees (graduate students and postdoctoral fellows), as well as a wide variety of outreach activities aimed at expanding and enriching the cancer systems biology community both within the university, in the larger scientific community, and among the public. Finally, the center will coordinate its research and outreach activities with those of other centers in the NCI Cancer Systems Biology network.

The Outreach Core of the UCI cancer systems biology center will promote cancer systems biology to the research community, targeting researchers and trainees at all career stages, and will disseminate advances and capabilities of cancer systems biology to the cancer research and broader communities. These goals will be met through a variety of activities including symposia, seminars, ?short courses?, interest groups, ?boot- camps?, a visiting scientist program, and an annual retreat. Included among the activities of the core will also be programs aimed at mentoring junior faculty, programs to provide undergraduate and pre-college students with exposure to cancer systems biology research, and activities to increase public awareness of the advances and capabilities of cancer systems biology. The core will monitor its effectiveness through periodic evaluation, and will coordinate and integrate with activities of the larger NCI Cancer Systems Biology consortium

Systems Biology refers to the integration into biology of ideas and methodologies from mathematics, engineering, computer science, physics, and chemistry, with the goal of deriving greater understanding from data?especially data that are complex, dynamic and/or high-dimensional. Systems biology makes frequent use of explicit, quantitative models, and concerns itself both with how useful models can be derived from data as well as how models can be used to generate hypotheses and drive the collection of new data. Modern biological and biomedical research are becoming increasing reliant on systems biology approaches, yet because the skills and insights necessary to implement such approaches come from so many different disciplines, it can be challenging for researchers to take full advantage of them. The goal of the Systems Biology Core is to enable skin biology researchers to incorporate systems biology in their research, thereby enhancing productivity and increasing research impact. The core will help skin biologists derive more meaningful models from data; build and analyze explicit, quantitative models; use models to interpret, analyze, and integrate data (including data generated by other cores); use models to generate and prioritize testable hypotheses about function; and better understand and utilize literature that draws upon systems biology ideas and approaches. Methodologies to be made available through the Systems Biology Core are especially well suited to building upon data from, and providing input into, the efforts of the imaging and genomics/bioinformatics cores. Strategies for achieving these goals include targeted workshops for skin biologists, inclusion of skin biologists in an annual systems biology retreat, systems biology ?clinics? at which skin biologists identify problems in need of attention, and individualized consultation. These strategies leverage the expertise and resources of three systems biology faculty with expertise in modeling and data analysis; long-standing experience in teaching interdisciplinary science; and a track-record of collaboration with skin biologists. It also leverages the infrastructure of a large campus-wide center devoted to systems biology, the Center for Complex Biological Systems.

Project Summary Effective mentoring relationships influence student professional development by shaping both the training experience and students? perspectives on their field. Yet few of those involved in the training of graduate students receive formal training in how to mentor. We herein propose a series of mentor training activities tailored to the faculty in our T32 training program in Mathematical, Computational and Systems Biology. Workshop sessions will be adapted from the Entering Mentoring curriculum developed by the Center for the Improvement of Mentored Experiences in Research (https://cimerproject.org/). In addition, we will use interactive, small group sessions and invited speakers to reinforce key concepts and foster mentor-mentor support and peer mentoring among our program faculty. We will also use the Strength Deployment Inventory assessment, a tool to identify mentor personality and leadership strengths and motivations, to help provide mentors with strategies for engaging with diverse mentees. Opportunities for sustaining these activities beyond an initial year are also discussed in the proposal. Over the long run, we believe these changes will help improve the mentee experience and enhance student retention.