University Of Illinois At Urbana-Champaign

NIH Research Projects · FY 2023 · 2019-09

Project Summary Large-scale networks of the human brain can be measured non-invasively using functional Magnetic Resonance Imaging (fMRI). While most previous work has focused on group descriptions of functional networks, recent findings suggest that the study of highly-sampled single participants can reveal novel aspects of brain organization specific to an individual. Here, we focus on atypical locations where an individual’s functional networks do not match the group, which we call network variants. Preliminary data demonstrates that network variants are present across all individuals, but differ in location, number, and network assignment. Variants are most often associated with systems of the brain linked to goal-directed “controlled” processing. This observation is intriguing, given that individual differences in control functions are known to be large and heritable, and in extreme cases can be central contributions to pathology in disorders such as schizophrenia. Based on these preliminary findings, we develop a model, wherein we suggest that stable factors (e.g., genetics, long-term experience) reprioritize the functions of cortical areas, leading to the creation of network variants, altered task activations, and behavior. Our goal is to test this model by examining the sources and consequences of variants. Given that variants are most associated with regions related to controlled tasks, we focus our tests on control- related activations and behavior. We will test the following hypotheses: (Aim 1) variants represent stable, heritable, endophenotypes for individual differences in brain organization, (Aim 2) variants relate to individual differences in brain activations in control tasks, and (Aim 3) variants relate to individual differences in behavior in control tasks. In Aim 1 we propose addressing the trait-like nature of variants by measuring variant stability across states, and the similarity of variant patterns across unrelated individuals, mono-, and dizygotic twins. In Aim 2, we propose using a precision fMRI approach to measure variant activations across a range of control- related task contexts. Finally, in Aim 3 we propose examining whether variants are related to differences in control-related behavior. This proposal is innovative: it adopts cutting-edge methods for reliably characterizing networks in single individuals to study atypical components of brain networks (rather than group descriptions) and provides a new window into possible mechanisms underlying individual differences in brain organization, activations, and behavior. This proposal will impact (1) basic science, by expanding our understanding of individual variability in brain networks and their relationship to brain function and behavior, and (2) translational research, by laying groundwork for the study of extreme forms of individual differences in control found in psychopathology, potentially with future utility in personalized medicine. Thus, this proposal addresses RDoC goals by investigating (1) individual differences at multiple levels (brain organization, physiology, and behavior), (2) genetic and environmental sources for individual differences, and (3) potential biomarkers of dimensional individual differences linked to psychopathology.

NIH Research Projects · FY 2026 · 2019-07

Abstract Multicellular organisms are made of numerous types of cells. While all cells in the adult animal originate from the fertilized egg, cellular machinery and organelles are organized uniquely in different cell lineages. This allows different types of cells to carry out specific functions. For decades, scientists have been focusing on how gene regulatory networks and signaling pathways control lineage specification and differentiation. Much less attention has been given to the remodeling of the cellular machinery and organelles during development. Whether intracellular remodeling can influence cell fate determination and cellular differentiation represents a key knowledge gap. In an effort to understand the mechanisms governing the oocyte-to-embryo transition (OET), which is crucial for reproduction, we have discovered novel remodeling mechanisms that act on cellular organelles and mRNAs in the oocyte. These include relocation of the proteasome, remodeling of the endoplasmic reticulum (ER), regulated mRNA-ER association, and RNA phase transition during the OET. Based on these findings, we propose to investigate the impact of ER remodeling on cell fate determination during early embryonic development, mitochondria remodeling during oocyte maturation, and RNA phase transition during the OET. By studying the remodeling of organelles and RNAs during early development, the proposed studies will fill fundamentally important knowledge gaps and open a new dimension to study post-transcriptional regulation during development.

NIH Research Projects · FY 2026 · 2019-07

Project Summary / Abstract Stem cells are critical cell populations that maintain tissue health and regenerative capacity. Understanding the mechanisms leading to the decline of stem cell function can provide unique insights into how their regenerative abilities can be enhanced and prolonged to facilitate healthy aging. The environment in which stem cells reside has a major impact on their function, with factors such as oxygen availability, inflammation, oxidative stress, and the presence of reactive aldehydes playing crucial roles. However, our understanding of these mechanisms is limited due to a lack of methods to non-invasively detect these biomarkers within native tissue environments with the requisite sensitivity and accuracy. Likewise, tracking stem cells in vivo without altering them represents another long-standing challenge. This renewal application aims to address these gaps through the development of innovative chemical biology tools. We will continue to leverage our expertise in molecular imaging and probe design to develop advanced and sensitive probes for non-invasive visualization of these key biomarkers, as well as the activity of aldehyde-processing enzymes which can be used as a proxy for stem cell detection at the cellular and whole-animal levels. Additionally, we will develop dual- functional probes to study the crosstalk between stem cells and their tissue environment, focusing on oxygen availability, inflammation, and other biomarkers that influence stem cell function and aging. Our approach offers an exciting opportunity to significantly advance our understanding of this fundamental life process and identify novel therapeutic targets to promote healthy aging.

NIH Research Projects · FY 2025 · 2019-06

Title: University of Illinois Veterinary Diagnostic Laboratory participation in Veterinary Laboratory Investigation and Response Network Project Abstract This proposal is to request funding to continuously support the University of Illinois Veterinary Diagnostic Laboratory (UI VDL) to participate in the Veterinary Laboratory Investigation and Response Network (Vet-LIRN) program. The UI VDL is a full-service American Association of Veterinary Diagnosticians-accredited state laboratory and is a member of the National Animal Health Laboratory Network and Vet-LIRN program. The lab has been in the Vet-LIRN program since 2017 and currently serves as a core source lab for the program. The lab commits to continuously participate in all Vet-LIRN-directed activities, which includes 1) responding to animal food or drug-related illnesses, 2) detecting multi-drug resistant bacteria and newly emerging viral pathogens, and 3) improving and validating diagnostic approaches. The funding will be utilized to maintain equipment and to purchase the required materials for conducting Vet-LIRN-related projects and research projects in microbiology. The well-equipped and staffed UI VDL is delighted to fuel our efforts to benefit research in veterinary science and the goals of One Health.

NIH Research Projects · FY 2025 · 2019-03

PROJECT SUMMARY/ABSTRACT Natural products are indisputably the most productive source of chemical matter for antibiotic development. Unfortunately, the pharmacological deployment of new natural products has been outpaced by the waning utility of approved antibiotics, especially those active against Gram-negative bacterial pathogens, Genomic technologies and synthetic biology are uniquely positioned to address this shortfall, and towards that critical goal, the previous project period developed a fully 6utomated, §,calable, and high-Ihroughput (FAST) pipeline for the discovery of Ribosomally synthesized and Post-translationally modified Peptides (RiPPs), RiPPs are a class of natural product covering nearly 50 known structural families. Despite their impressive structural and functional diversity, RiPPs are united by a common biosynthetic strategy. A gene-encoded precursor peptide is comprised of an N-terminal leader region, providing a binding site for the modification enzymes, and a C-terminal core region, which receives all of the post-translational modifications. This renewal project builds on our previous success in unlocking the potential of RiPPs as a source of new antibacterials. For this project, we propose three interrelated but independently achievable specific aims. Aim 1 addresses pitfalls of the FAST-RiPPs procedure uncovered during the previous project period. Here, we will enhance our ability to achieve high titers of any desired RiPP structural class. Among others, solutions to the challenge of obtaining mature products involving radical S-adenosylmethionine-dependent enzymes are proposed. Aim 2 develops the ways and means to prioritize RiPPs with a high probability of displaying antibacterial activity. Lastly, Aim 3 addresses the grand challenge of predicting ring patterns directly from primary sequence for multicyclic RiPPs. With several RiPP classes associated with multimacrocyclic scaffolds and often encoding numerous macrocycle donor and acceptor residues in the core region, determining the structural outcome of the enzymatic pathways has been impossible. However, with advances in bioinformatics, artificial intelligence (Al), and new ring patterns discovered as a consequence of a functional FAST-RiPPs pipeline, a solution to this problem becomes feasible. Given their proven success rates from the previous project period, including the discovery of a potent anti-Klebsiella compound, lanthipeptides serve as our testbed for Al algorithmic development. This project blends cutting-edge Al, synthetic biology, biofoundry, and analytical chemistry techniques with innovative solutions to heterologous expression deficiencies. We further will engineer broad host range plasmid compatibility to overcome the need to reclone pathways when a heterologous host is deemed insufficient. Success on this project will have a profound impact on the synthetic biology community and pharmaceutical industry.

NIH Research Projects · FY 2025 · 2018-09

Project Summary Fertility depends on successful fertilization and early development, processes that occur in the oviduct. Common therapies for human infertility, such as in vitro fertilization and intracytoplasmic sperm injection, are expensive and increase the risks of a variety of problems. More knowledge of how the oviduct interacts with sperm, the cumulus-oocyte complex (COC), and the developing embryo may improve fertility and reduce the need for therapies or lead to the development of improved therapies (i.e. improvements in IVF). The oviduct serves as a reservoir for sperm, after semen deposition and before fertilization. Binding to the oviduct maintains sperm viability and suppresses motility. Sperm are released to move to the upper oviduct (ampulla) to fertilize oocytes. There are many gaps in this model of sperm-oviduct interaction but our studies have begun to fill some of these gaps. We have used a glycomic approach to screen hundreds of glycans and found that glycans with affinity for porcine sperm have either of two motifs, sulfated Lewis X trisaccharide or branched 6- sialylated complex glycans. We also identified two candidate receptors for both glycans on the sperm membrane, PKDREJ and ADAM5, that were not known to bind glycans. Notably, mouse sperm deficient in PKDREJ and other ADAMs do not accumulate beyond the utero-tubal junction, but it is not known if this is due to a problem in binding and retention in the oviduct. Remarkably, if these glycans are immobilized on beads or microscope slides, they can extend sperm lifespan, much like binding to oviduct cells prolongs the lifespan of sperm. Finally, we found that COCs secrete progesterone that signals sperm release from the lower oviduct by inducing hyperactivation so sperm can move toward the site of fertilization. The Specific Aims of this renewal will provide a mechanistic understanding of how sperm bind the oviduct, how binding prolongs sperm lifespan, and how these results may be translated to improve IVF. Aim 1: To determine the function of PKDREJ and ADAM5 in sperm by blocking each protein and mutating each gene in swine. Sperm from pigs that have mutations in these genes have been produced. Sperm that are deficient in each of these proteins will be examined to determine if their ability to bind oviduct cells and their fertility are affected. Aim 2. To determine if sperm binding to glycans diminishes oxidative phosphorylation and the citric acid cycle to lengthen sperm lifespan. Sperm bound to immobilized glycans will be examined to ascertain the specific metabolic changes that are induced and the intracellular signaling that leads to these changes. Aim 3. To determine if oviduct glycans select superior sperm for storage and in vitro fertilization. We will examine whether sperm selected by glycan adhesion have improved characteristics themselves and also produce embryos that more closely resemble in vivo-produced embryos by comprehensive analysis of embryo transcriptomes and methylomes. The completion of these Specific Aims will provide important keys to resolving how sperm bind to the oviduct, are stored in the oviduct, and are released in response to the COC. This fundamental information could be used to develop simpler, safer, and less costly assisted reproductive technologies.

NIH Research Projects · FY 2024 · 2018-04

Project Summary Phosphonic acids, defined by the presence of stable carbon-phosphorus (C-P) bonds, are an underexploited group of compounds with great biomedical promise, which stems from (1) a proven track record in clinical and commercial applications, (2) an immense diversity of cellular targets and modes of action (3) availability of a suite of research tools that allow facile discovery and characterization, (4) a proven reservoir of novel, unchar- acterized members of the class, and (5) unusual biosynthetic pathways whose characterization has enhanced and expanded our knowledge of fundamental biochemistry. This research project takes advantage of these fea- tures, focusing on phosphonate natural products with useful bioactivities and interesting chemical features, as well as the discovery of novel phosphonates. The long-term goals of the project include elucidation of the genes, biosynthetic pathways, resistance mechanisms and bioactivities of selected phosphonates, as well as charac- terization of novel enzymatic activities involved in their synthesis. The specific aims for the proposed funding period are: (1) characterization of the biosynthesis and bioactivity of phosphonothrixin and related molecules, (2) characterization of the biosynthesis and bioactivity of phosphonates produced by host-associated enterobac- teria, and (3) development of improved genome-mining tools for phosphonate discovery. Relevance This research has the potential to discover phosphonate natural products with useful bioactivities and interesting chemical features. Moreover, characterization of the genes, enzymes and biosynthetic pathways needed for production of these compounds is likely to reveal novel biochemistry that significantly expands our understanding of the chemical transformations catalyzed by microbes, while paving the way for creation of strains that overpro- duce useful molecules and their derivatives.

NIH Research Projects · FY 2025 · 2017-09

Vertebrate and invertebrate neural progenitors are temporally patterned to generate a great diversity of neural types in a birth-order dependent manner. Series of temporal transcription factors (TTF) were found to be sequentially expressed in Drosophila neuroblasts, and they are proposed to form transcriptional cascades to control the sequential generation of different neural types. However, whether the cross-regulations inferred from mutant phenotypes are direct transcriptional regulations haven't been demonstrated. Furthermore, the cross-regulations among TTFs are often not sufficient for the temporal transitions, suggesting other mechanisms are at play to regulate the temporal progression. We use the Drosophila medulla neuroblasts to study these questions. In the previous R01 period, we identified molecular mechanisms controlling transitions to the Slp and Ey temporal stages, and also identified a comprehensive list of novel temporal transcription factors through single-cell RNA sequencing. In this renewal application, we present our preliminary data of single-nuclear ATAC seq, which revealed the dynamic chromatin accessibility during temporal patterning of medulla neuroblasts. Through analyzing the differentially accessible regions, we identified the possible enhancers controlling the temporal expression patterns of TTF genes. Through integration of scRNA-seq and snATACseq and a combination of reporter assays, genetic analysis and Dam-ID experiments, we propose to elucidate the transcriptional regulatory networks controlling the sequential temporal transitions in great detail. Furthermore, we found that different epigenetic factors are required at different steps of temporal patterning. We propose to further examine how they regulate the dynamic chromatin accessibility and how they are recruited to specific target genes during temporal patterning. Finally, we propose to examine the fundamental molecular mechanisms that coordinate the growth/proliferation with TTF cascade progression, and will test our hypothesis that early TTFs have different roles in controlling growth/proliferation than late TTFs through a combination of approaches.

NIH Research Projects · FY 2025 · 2017-07

Significance: The ability to measure the molecular mechanisms of neuronal communication at the nanometer spatial scale will have enormous impact on basic bioscience and likely to future clinical neuroscience. In particular, AMPA- and NMDA-type glutamate receptors (known as iGluRs) are dynamically involved in neuron- to-neuron communication across the thin (≈30 nm) synapse; when dysregulated, neurodegenerative diseases result, such as Alzheimer’s and Parkinson’s diseases. We—and others—have tracked these events with nanometric resolution using super-resolution fluorescence microscopy (SRFM). Using small probes—quantum dots (≈12 nm diameter) and other photostable fluorophores, developed in our lab in the preceding grant—we came up with some surprises. We find that a large fraction of the AMPARs reside in the synapse where their mobility is restricted; during long-term-potentiation (LTP, a molecular underpinning of memory formation), we’ve quantified their numbers and find during their maintenance phase that their lateral diffusion is rare; NMDARs have extra-synaptic nanodomains which may keep their numbers from rising during LTP. But are these, and other results, correct? To validate these preliminary results, we will measure the placement and diffusion of the iGluRs, primarily AMPARs, using three different SRFM techniques, each one having its own advantages and disadvantages. We will also determine the 3D-orientation of the synapse, the effect of probe size and type, the details of LTP activation, and quantitatively determine the number of iGluRs at each synapse. The results between the three techniques will be compared. Innovation: Each SRFM technique has new aspects, particularly with respect to neuroscience. First, we will improve the PALM/STORM technique (one type of SRFM) to test the distribution and dynamics of iGluRs more accurately. We will use new probes—nanobodies and scFv’s—against post-synaptic proteins and iGluRs, and test new sQDs and new cross-linking reagents against iGluRs. We will also determine the orientation and position of the synaptic zone by labeling neuroligin and various presynaptic proteins, such as Bassoon and RIM1/2, first under basal conditions and then with chemical LTP (cLTP). Second, we will use and develop PAINT, another form of SRFM, which has recently been shown to have a 100× increase in speed with excellent spatial resolution—≈5 nanometers in 0.2 sec. We will show that quantitative-PAINT can be applied to fixed neurons and can be used to measure cLTP on an individual synapse. And for the first time, we will apply PAINT to a living neuron under physiological conditions to measure AMPAR dynamics. With PAINT, we will be able to test how many iGluRs there are per synapse, whether they are synaptic or extra-synaptic, and how the number of iGluRs change with cLTP. Third, we will utilize a fluorogenic activating protein (FAP) with iGluRs and show that the number of receptors can be measured in living neurons with nanometric resolution, no background, and potentially fast response to cLTP. This method will therefore provide another test of iGluR structure & dynamics.

NIH Research Projects · FY 2026 · 2017-07

Project Abstract Chronic liver diseases are on the rise and are associated with almost $100 billion in healthcare costs in the United States. Since the liver is a primary site for detoxification and metabolizes a variety of chemicals, prescription drugs, and nutrients, it is prone to constant damage. To cope with the insults, the liver has inherent mechanisms, including division of labor, polyploidy, and injury-associated liver regeneration. Although liver metabolism and liver diseases exhibit sexual dimorphism, studies focused on understanding sex differences in liver injury and regeneration are lacking. The nuclear receptor, Constitutive Androstane receptor (CAR), controls detoxification, and several metabolic pathways and is linked to liver growth. But spatiotemporal and sex-specific CAR-mediated regulation remains unexplored. We still do not know if and how CAR (i) regulates zonation and if CAR targets distinct genes in the different zones of the liver, (ii) controls polyploidy and injury- associated regeneration, (iii) influences estrogen receptor α (ERα)-mediated signaling, and (iv) contributes to the sex differences seen in liver metabolism and functions. This study is designed to address these gaps. In this renewal, we combine high throughput analysis of transcriptomes and cistromes using a novel epitope-tagged FLAG-CAR mouse and different chemical-based liver injury models to decipher how CAR orchestrates various aspects of hepatic metabolism and functions. In specific aim 1, we will determine if CAR is necessary for metabolic maturation and maintaining heterogeneity of hepatocytes, whereas in specific aim 2, we will determine the role of the CAR- ERα axis in regulating sex differences in polyploidy and regeneration in the liver. The long-term objective of these studies is to gain comprehensive understanding of the molecular mechanisms that integrate metabolic functions and liver regeneration and growth. Our proposed studies will uncover new insights and elaborate on a fundamental aspect of CAR in controlling the metabolic fitness of hepatocytes. This knowledge, in turn, can be maneuvered to prevent and or treat liver diseases.

NIH Research Projects · FY 2026 · 2017-05

PI, White, M.C.    R35 GM 122525    1  Project Summary 2  3  The atomistic change of C(sp3)–H to C(sp3)–O, –N, or –C can profoundly impact the biological function and 4  physical properties of small molecules. Traditionally, introducing these functionalities relies on functional group 5  transformations from pre-oxidized carbon-heteroatom precursors. This approach limits the direct installation of new 6  functionality into complex molecules, often necessitating de novo synthesis that is impractical for rapid exploration of 7  biological function. Our proposal aims to provide selective C(sp3)–H functionalization reactions that install O, N and 8  C in the hydrocarbon scaffold of complex molecules. This will enable late-stage functionalizations that expedite drug 9  discovery processes, streamline total syntheses, and empower exploration of natural products as drug candidates. 10  Our group has shown that C(sp3)–H bonds in complex molecules can be distinguished based on their 11  electronic, steric, and stereoelectronic properties, resulting in a paradigm shift within the chemistry community that 12  prior to 2007 viewed aliphatic C–H bonds as preparatively indistinguishable. To do this, we have discovered and 13  commercialized iron and manganese PDP-based catalysts for C(sp3)–H oxidations; palladium(II)/sulfoxide catalysts 14  for allylic C–H functionalization; and manganese phthalocyanine catalysts for both intra- and intermolecular C(sp3)– 15  H aminations. These catalysts proceed with excellent levels of reactivity and selectivity in complex molecule settings, 16  without the need for directing groups. The late-stage functionalization approach that has emerged from this work has 17  been utilized in both industrial and academic settings. Building on this considerable foundation, we will undertake 18  major challenges required to broaden the application of late-stage functionalization in chemical synthesis and drug 19  discovery. We will innovate new base-metal complexes for aliphatic C–H oxidations that increase chemoselectivity 20  for tolerance of π-functionality and unprotected alcohols, as well as explore catalyst chiral recognition through non- 21  bonding interactions. These advances will make possible new reactions such as oxidative alkylations and catalyst- 22  controlled asymmetric induction and site-divergence. We will develop new base-metal complexes for intermolecular 23  C–H aminations and alkylations with unprecedented selectivities, and discover new ligand types amenable to 24  asymmetric induction. New palladium(II)/sulfoxide catalysts will be invented with an emphasis on introducing 25  functionality in complex settings. Cross-coupling reactions will be developed where O and N are introduced as part of 26  complex fragments. Additionally, asymmetric C–H functionalizations that feature catalyst-controlled 27  diastereoselectivities in substrates with pre-existing stereogenic centers will be advanced. Collectively, this program 28  will change the way synthetic chemists make and diversify complex molecules in pursuit of therapeutics, metabolites, 29  and biological probes.

NIH Research Projects · FY 2025 · 2016-09

This is a competitive renewal application (1) to continue to follow children in the Illinois Kids Development Study (IKIDS) who are participants in ECHO, and (2) to continue recruiting new pregnant women into the IKIDS ECHO cohort. We will continue recruiting participants through partnerships with the Champaign-Urbana Public Health District (CUPHD) and Carle Foundation Hospital. Specifically, we propose to enroll 660 additional pregnant women (and their conceiving partners, if available) through these partnerships with Carle Hospital and CUPHD during the next phase of ECHO. We will rely heavily on community engagement, input from an established Community Advisory Board, and feedback from focus groups to develop recruitment and retention strategies that are effective for both retaining our current participants and recruiting, enrolling, and retaining new pregnant participants. A subset of these participants who report a moderate to high likelihood of becoming pregnant again will be enrolled in the planned preconception pilot study. Our scientific aims will be addressed in a series of ECHO Concept Papers and will build on our previous work investigating the impacts of maternal prenatal stress or chemical exposures on birth outcomes and neurodevelopment. Leveraging data from multiple ECHO cohorts will allow us to apply state-of-the-art mixtures methods to investigate the impact of multiple chemical and non-chemical stressors on birth outcomes (gestational age at birth; birth weight; anogenital distance) and child cognitive development (specific domains from the NIH toolbox cognitive battery; measures of language development). We will also use novel approaches to evaluate the ability of a healthy maternal diet to mitigate the negative impact of these exposures on our outcomes of interest. Our hypothesis is that multiple prenatal stressors and/or chemical exposures jointly impact child neurodevelopment and birth outcomes, and these impacts can be mitigated by a healthy diet. We will use multiple measures of prenatal psychosocial stress from the core ECHO protocol (Aim 1), multiple studied and novel phthalates/replacements and phenols from the ECHO-WC- HHEAR novel chemicals analysis (Aim 2) or both chemicals and stressors in our mixtures models. To assess the impact of diet, we will use a novel approach in which we will include multiple dietary components calculated using established diet quality indices, together with multiple measures of maternal psychosocial stress or multiple chemicals, to understand the cumulative effects of the diet/stress or diet/chemical mixture and to evaluate if particular components of healthier diets can lessen or negate adverse associations of maternal stress or chemical exposures with child cognition or birth outcomes. Lastly, an exploratory aim will evaluate associations of maternal preconception stressors with (1) birth outcomes and (2) neurodevelopment during infancy.

NIH Research Projects · FY 2024 · 2016-09

PROJECT SUMMARY This is a competitive renewal application (1) to continue to follow children in the Illinois Kids Development Study (IKIDS) who are Level 2 participants in ECHO, and (2) to continue recruiting new pregnant women into the IKIDS- ECHO cohort. A key goal of our continued recruiting effort is to increase the racial/ethnic and income diversity of our cohort through new recruiting partnerships with community agencies – the Champaign-Urbana Public Health District (CUPHD) and Promise Health Care (our local federally qualified health center) – that serve a primarily low-income, racially and ethnically diverse population of pregnant women. Specifically, we propose to enroll 660 additional pregnant women (and their conceiving partners, if available) through our partnerships with these two entities during the next phase of ECHO. We will rely heavily on community engagement, input from an established Community Advisory Board, and feedback from focus groups to develop recruitment and retention strategies that are effective for both retaining our current Level 2 participants and recruiting, enrolling, and retaining new pregnant participants. A subset of these participants who report a moderate to high likelihood of becoming pregnant again will be enrolled in the planned preconception pilot study. Our scientific aims will be addressed in a series of ECHO Concept Papers and will build on our previous work investigating the impacts of maternal prenatal stress or chemical exposures on birth outcomes and neurodevelopment. Leveraging data from multiple ECHO cohorts will allow us to apply state-of-the-art mixtures methods to investigate the impact of multiple chemical and non-chemical stressors on birth outcomes (gestational age at birth; birth weight; anogenital distance) and child cognitive development (specific domains from the NIH toolbox cognitive battery; measures of language development). We will also use novel approaches to evaluate the ability of a healthy maternal diet to mitigate the negative impact of these exposures on our outcomes of interest. Our hypothesis is that multiple prenatal stressors and/or chemical exposures jointly impact child neurodevelopment and birth outcomes, and these impacts can be mitigated by a healthy diet. We will use multiple measures of prenatal psychosocial stress from the core ECHO protocol (Aim 1), multiple studied and novel phthalates/replacements and phenols from the ECHO-WC-HHEAR novel chemicals analysis (Aim 2) or both chemicals and stressors in our mixtures models. To assess the impact of diet, we will use a novel approach in which we will include multiple dietary components calculated using established diet quality indices, together with multiple measures of maternal psychosocial stress or multiple chemicals, to understand the cumulative effects of the diet/stress or diet/chemical mixture and to evaluate if particular components of healthier diets can lessen or negate adverse associations of maternal stress or chemical exposures with child cognition or birth outcomes. Lastly, an exploratory aim will evaluate associations of maternal preconception stressors with (1) birth outcomes and (2) neurodevelopment during infancy.

NIH Research Projects · FY 2026 · 2016-06

Project Summary/Abstract This proposal aims to substantially advance two frontier research areas, Molecular Prosthetics and Automated Small Molecule Synthesis, and thereby have a major impact on human health. The first half targets the development of a new class of molecular prosthetics that replace missing biochemical reactions. Our lab has recently demonstrated in animals and in people that small molecules can replace the function of deficient proteins, thus operating as prostheses on the molecular scale. We further illuminated specific mechanisms that permit imperfect functional mimicry to be sufficient for substantial physiology restoration due to the inherent robustness of living systems. In this proposal we will launch a new research direction to find small molecules that replace deficient enzymes. There are more than 100 human diseases linked to loss of enzyme function, and we will specifically target three examples: Ornithine Transcarbamylase Deficiency, Argininosuccinate Lyase Deficiency, and Hereditary Tyrosinemia Type 1. These diseases have two features in common that we propose render them susceptible to this approach: 1) a high concentration of the substrate for the missing enzyme, or an upstream precursor, builds up in the blood and/or tissues, and 2) the corresponding substrate has unique chemical reactivity. We hypothesize that these two features will permit imperfect small molecule reagents to serve as effective functional surrogates for missing enzymes in human blood plasma and in mouse models. The second half targets new molecular lego kits for automated synthesis of two functionally-rich classes of natural products: lipids and polycyclic terpenoids. Both classes perform many biological and industrial functions, yet remain inherently challenging to synthesize. Building on our recent development of a fully automated lego-like platform for small molecule synthesis, we plan to create a lego kits for on-demand preparation of both classes of compounds. Parallel retrosynthetic analysis showed that preparation of ~130 known polyunsaturated fatty acids requires only 26 building blocks, which we will prepare. We will also develop two new Csp3-C bond forming methods to iteratively assemble building blocks, and a Nextgen synthesis machine to render this process fully automated. We will apply this platform to better understand molecular prosthetic ion channels. We also plan to combine modular lego-like construction of linear molecules with cyclization-promoting self-assembled resorcinarene capsules to create a highly efficient and flexible lego kit for polycyclic terpenoids. To this end, we will define new structure-cyclization relationships, characterize their underpinnings, and leverage them to achieve efficient syntheses of complex polycyclic terpenoid natural products. Collectively these studies will push the frontiers of chemical biology and organic synthesis and open new frontiers for medicine.

NIH Research Projects · FY 2025 · 2016-06

Project Summary / Abstract Biological membranes are needed by all life forms. These lipid bilayers separate the inside and outside of the cell and provide the separation between internal compartments. As such, they are the site for cellular recognition and communication and provide the home to a host of proteins that mediate signaling, catalysis, the generation and transduction of energy and the import and export of molecules. Despite this central role in life, membranes and membrane proteins have often been difficult to study using the normal tools of biochemistry and molecular biology. Membrane proteins display altered activity or are inactive when removed from their native lipid environment. Likewise, revealing the fundamental molecular recognition events involved in forming complex multi-component architectures at the membrane surface requires new methodologies. Nanodiscs, self-assembled nanoscale lipid bilayers solubilized by an amphipathic scaffold protein developed in our laboratory, have served to enable multiple new discoveries in these arenas. Under continued MIRA support, we will use the Nanodisc system to provide novel biochemical and biophysical paths to the realization of the molecular mechanisms involved in signaling, hormone biosynthesis, drug metabolism, the epitaxial presentation of oligomeric viral antigens and the membrane proteins of the synaptic junction. Systems under investigation include: The human cytochrome P450 systems involved liver and adrenal metabolism; the Ras GTPases involved in cancer signaling; vinculin, a critical component in the control of cellular migration, the proteins of the synaptic junction that bind oligomeric peptides, the ability of Nanodiscs to order complex oligomeric surface antigens and the biophysics of Nanodisc assembly.

NIH Research Projects · FY 2025 · 2016-04

ABSTRACT More than two million Americans have undergone bariatric surgery over the last decade; given the obesity epidemic, this number will continue to rise. Since 2018 of the ~ 250,000 yearly bariatric procedures performed in the United States, 72% are sleeve gastrectomy (SG) and 21% Roux-en-Y gastric bypass (RYGB). Although these surgeries provide the most successful long-term treatment for obesity, they double the risk of developing alcohol use disorders (AUD). The precise mechanism(s) underlying an increase AUD risk is uncertain, but in our previous NIH-funded research in women who underwent these surgeries (AA024103), we demonstrated that both SG and RYGB cause profound changes in alcohol pharmacokinetics (PK) and sensitivity to the subjective effects of alcohol; both of which can increase AUD risk. RYGB and SG doubled peak blood alcohol concentrations when consuming the same dose as before surgery. By studying PK after SG, we also help clarify that most alcohol first-pass metabolism (FPM) occurs in the stomach, not the liver (at least in women), providing a plausible mechanism for increased alcohol-related liver disease and AUD after surgeries that reduce the stomach. In people who did not undergo SG/RYGB, drinking alcohol with a meal increases FPM and the alcohol elimination rate (AER), thus reducing alcohol bioavailability and intoxication. However, the effects of food on alcohol PK after SG are unknown. SG alters nutrient absorption leading to earlier and higher glycemic peaks concomitant with exaggerated postprandial insulin rises that can trigger postprandial hypoglycemia. Because alcohol inhibits gluconeogenesis, we posit that drinking alcohol with food will increase the risk for hypoglycemia after SG. In addition, there are remarkable sex-related differences in alcohol PK, but previous bariatric studies included only women or very few men to determine sex differences. Therefore, the primary goal of the proposed study is to determine sex-related differences in the impact of SG on the PK (Aim 1), subjective effects (Aim 2), and glycemic effects (Aim 3) in the fasted versus prandial state when alcohol is ingested or given intravenously clamped (the gold standard to measure AER and acute alcohol tolerance). We will use a cross-sectional study to compare participants who underwent SG surgery 1-5 years ago with matched non-operated controls (both sexes). Our main hypotheses are that compared to controls, in the SG group, food will 1) increase less FPM (particularly in men) and decrease less the sedative effects of ingested alcohol, 2) amplify alcohol-hypoglycemia and acute tolerance to the sedative effects when alcohol is given IV (in the clamp). This project will answer the questions of whether there are sex-related differences in the impact of SG on alcohol’s PK and pharmacologic effects, whether drinking alcohol with a meal is effective or counterproductive post-SG (considering risk for hypoglycemia) and clarify the site of FPM in men. Findings from this study will contribute to evidence-based recommendations on the impact of SG on alcohol-related toxic effects and could help expand the knowledge base of sex-related differences in human alcohol PK.

NIH Research Projects · FY 2025 · 2016-04

A quantitative understanding of the tissue microenvironment (TiMe) is critical for advancing biomedical knowledge and healthcare, ranging from regenerative medicine to managing the burden of cancer. To train productive bioengineering leaders, education in three technological areas is essential: (a) sensing and imaging to measure biochemical and biophysical properties, (b) bioengineering to recapitulate the TiMe, and (c) computational modeling and analytics to gain insight. Accordingly, we propose to continue the TiMe training program wherein predoctoral students integrate the three technological approaches with TiMe-related biological contexts of disease and development to launch successful research careers. Training includes four core components—Curricular Activities to ensure technical depth and critical thinking with apposite breadth across disciplines, Extracurricular Activities to develop pragmatic skills, Professional Development to empower trainees to become research leaders, and Career Development to position trainees to make lifelong contributions to society. The activities are structured to streamline education and efficiently focus on research, with the awarded doctoral degree to include a special designation (concentration in TiMe). This past project period was our second and progress was made in refining the program, its activities and evaluation. Building upon the success of trainees (all ten graduated are in biomedical research careers, ~5.5. papers per trainee, and significant follow-on funding and awards), we propose to continue student development activities, add a novel hands-on education component based on a newly constructed laboratory and emphasize emerging scientific topics including machine learning, imaging for spatial biology, and design thinking. Illinois has exceptionally strong disciplinary programs, highly effective scientists and mentors as faculty, appropriate facilities and unique resources in each of these technological areas. The TiMe Training Program is distinctly advantaged by our strong history of successful graduate training, including a culture of productive collaboration, a 20-year old Department of Bioengineering, and strong institutional support (matching direct support - $1.5 M and $2.9 M of total support). Forty faculty will serve as faculty mentors and other university faculty with expertise in pedagogy, evaluation and professional development, provide critical resources for the program. We propose to educate at least ten trainees (four from NIH support and six matching slots from Institutional support) for up to two years each. Four NIH-supported trainees will be appointed annually from a strong applicant pool across campus. Traditional education will further be enhanced by co-mentored research with possibilities of translational opportunities via a new engineering-based College of Medicine. Outcomes will be rigorously evaluated throughout the program to improve training, to guide administrative decision-making and to disseminate best practices. The vision, expertise, and infrastructure of the Illinois TiMe Training Program will ensure that trainees selected from a large and well-qualified graduate community will provide sustained research contributions to benefit public health.

NIH Research Projects · FY 2026 · 2016-02

This is a competing continuation application to renew the Summer Undergraduate Research Experience in Toxicology (SURE Tox) program at the University of Illinois Urbana-Champaign (UIUC). The Program, established in 2016, provides high quality research experiences for undergraduate students during the summer academic break. The program involves active participation by faculty preceptors from 8 departments and 5 colleges at the UIUC, all of whom have been selected based on their commitment to conducting toxicology and environmental health research, active research funding, and positive history of training students. The SURE Tox Program provides a mechanism for bringing undergraduate students into the important field of environmental and toxicology research, providing them with a positive research experience that will foster their interest in entering graduate and/or professional school. Further, the proposed design of the SURE Tox Program fosters interactions between undergraduate students, faculty, graduate students, postdoctoral fellows, and other summer trainees working in the important field of environmental health and toxicology. The proposed SURE Tox Program will enroll 8 undergraduate students who will spend 8 weeks over the summer in the Program. The specific goals of the SURE Tox Program are to: 1) match participants with faculty preceptors and peer-mentors (graduate students or postdoctoral fellows) who will direct the student to complete a hypothesis-driven project in the field of toxicology and environmental health; 2) help each student learn laboratory techniques and research skills; 3) provide training in research ethics and methods for enhancing reproducibility; 4) train students in scientific writing; 5) train students to prepare scientific talks and posters and to present their work at scientific meetings; 6) provide networking opportunities for students to meet other students and faculty members in toxicology and environmental health research; 7) provide students with information on academic, government, and industry careers in toxicology and environmental health; and 8) provide students with information and training in applying to graduate and professional schools. At the conclusion of the program, each student will present her/his work in platform and poster sessions at the STEM Career Exploration and Symposium hosted by UIUC. Overall, the SURE Tox Program will provide a unique opportunity for undergraduate students to obtain training and research experience in the field of toxicology and environmental health at a research-intensive university with outstanding toxicology programs.

NIH Research Projects · FY 2025 · 2015-04

PROJECT SUMMARY The ability to decipher meaning from degraded sounds is critical for everyday hearing. A key strategy to extract buried signals is to integrate stored acoustic representations with the incoming sound stream. Such top- down/bottom-up interaction appears to be a fundamental feature in sensory systems. Indeed, disruptions of such processes may be involved in disorders such as autism and dyslexia. Unfortunately, little is known about the mechanisms by which top-down information modulates sensory function. Here, we propose a circuit-level analysis of a massive descending pathway from the auditory cortex to the inferior colliculus (IC) which is thought to be important for top-down modulation. Although this pathway has been shown to be critical for many processes important for auditory perception, how it supports such diversity of function is not known. During the last funding period, we uncovered an unexpected degree of heterogeneity in this pathway. For example, we observed that neurons in the two cortical layers from which this pathway is derived, layer 5 (L5) and layer 6 (L6), have distinct physiological, morphological and connectivity patterns. L5 neurons receive direct thalamic input, burst when stimulated and send projections containing giant terminals to the lateral cortex (LC) of the IC. L6 neurons receive sparse local input, but sample from a broad area of the cortex and end in small terminals on the distal rim of the LC. These data suggest that L5 neurons send a rapid and secure signal to the LC, while L6 neurons modulate LC function based on broad multisensory integration. We also found that the corticocollicular projections interdigitate with periodic neurochemical clusters (“patches” and “matrix”) in the LC and that the presence of this patch/matrix system governs virtually all input and output to and from this structure. These findings raise several questions that will be addressed in the current proposal. First, how does the L5/L6 system interface with the neurochemical and connectional mosaic comprising the LC? To address this question, we will use machine learning tools to parse the neurochemical cell classes in the LC, and then use a novel form of Cre-dependent trans-synaptic tracing to map parallel pathways originating in L5 or L6 and ending at one of the many targets of the LC. Second, we will examine the impact of L5 and L6 terminals on LC neurons using optical and electrophysiological approaches to determine the relative impacts and geometry of these inputs. Third, we will determine what messages are sent by L5 and L6 to the LC by imaging their axons in response to auditory and non-auditory stimulation using a novel microprism-based two-photon imaging approach in awake mice. We can thus determine if L5 and L6 send distinct messages to the LC, and whether the messages vary across the patch/matrix topography. Therefore, by leveraging the patch/matrix organization to parse the dense thicket of inputs and outputs to and from the LC, this work will shed light on mechanisms of top-down modulation in the auditory system. In doing so, it will provide a paradigm for understanding diseases involving disruptions in top-down/bottom-up integration, such as dyslexia and autism.

NIH Research Projects · FY 2026 · 2014-08

ABSTRACT The hematopoietic system offers an ideal biological system to develop tools to study how dynamic matrix, metabolic, and cellular selection pressures influence stem cell fate. Hematopoiesis is the process where the body’s blood and immune cells are generated from a small number of hematopoietic stem cells (HSCs). HSC quiescence, self-renewal, and differentiation take place in, and are regulated by, unique regions of the bone marrow termed niches. HSCs are also the functional unit of therapeutic bone marrow transplants following myeloablative therapies. A major goal of the hematology community is to selectively expand HSCs without sacrificing a subpopulation of quiescent, long-term repopulating HSCs required for life-long hematopoiesis. Yet while the marrow is known to change substantially across the lifespan, studies of the influence of niche remodeling on HSC behavior are in their infancy. The long-term goal of this Stimulating Hematology Investigation New Endeavors (SHINE) project is to advance tissue engineering platforms to achieve HSC expansion without exhaustion. In the previous funding period (R01DK099528) we established a tissue engineering ecosystem to examine the coordinated impact of niche-inspired biophysical signals on HSC fate. We developed microfluidic tools for extended culture of primary murine HSC in miniaturized gelatin hydrogels containing marrow-inspired gradients of stiffness, niche cells, and soluble vs. immobilized biomolecules We showed the kinetics of HSC- niche cell crosstalk can be manipulated via biomaterial design to enhance retention of quiescent HSCs. Mesenchymal stem cells (MSCs) within the marrow are increasingly believed to dynamically remodel the niche and provide powerful signals to influence HSC fate. Hence, the objective of our renewal is to use an innovative granular biomaterial to investigate the coordinated action of MSC remodeling and hypoxic stress on functional changes in HSC activity. We hypothesize the mosaic nature of the bone marrow can be replicated as jammed assemblies of cell-laden hydrogel microdroplets. We will create granular hydrogels from MSC and HSC microdroplets to trace the consequences of matrix remodeling, metabolic constraint, and MSC-HSC crosstalk on HSC fate. To accomplish this goal we will first establish an engineered model of MSC-mediated niche remodeling (Aim 1). We will define shifts in HSC-MSC crosstalk under hypoxia (Aim 2). And we will evaluate a mosaic granular hydrogel model of the multicellular marrow (Aim 3). Granular hydrogels provide the technical basis for creating mosaic niche analogs necessary to study remodeling mediated effects on HSC activity. The well- characterized murine hematopoietic system provides a rigorous framework to evaluate ex vivo regulatory processes in niches whose rarity and complexity limit direct in vivo study. Consistent with score-driving criteria of the SHINE program, we will develop essential tools to rigorously assess how dynamic processes of matrix remodeling and HSC-niche cell crosstalk inform HSC stemness that is directly relevant to the NIDDK mission.

NIH Research Projects · FY 2026 · 2011-12

All cancers must solve the problem of elongating telomeres to achieve replicative immortality. Roughly 90% of all cancers accomplish this task by reactivating the expression of the telomerase reverse transcriptase (TERT) gene, and a large fraction of them achieve this transcriptional dysregulation by mutating regulatory sequences in the TERT promoter. In the previous two funding segments, we have discovered that the molecular function of these highly recurrent mutations is to recruit specifically the transcription factor (TF) GABP to TERT promoter. Understanding and targeting the regulatory network of GABP thus provides an unprecedented opportunity to develop effective strategies for treating numerous cancer types. Despite the clear significance of this opportunity, however, there still remain several urgent questions surrounding the TERT promoter mutations and GABP function, partial answers to which we have recently uncovered. This renewal application thus seeks to integrate rigorous computational and experimental analyses to initiate a novel framework for dissecting the transcriptional regulation of telomere-associated genes and for circumventing potential resistance mechanisms against precision therapies targeting the GABP network. The long-term goal of our research program is to establish a rigorous computational framework for understanding aberrant transcriptional and epigenetic networks in cancers and to apply the resulting knowledge to develop effective therapeutic interventions that can a priori predict and avoid potential resistance mechanisms. The objective of the current renewal application is to initiate a new direction in this endeavor and develop rigorous approaches for dissecting the co-regulation of several hallmarks of cancer by TF modules involving GABP. We will accomplish our objective by pursuing the following aims: (1) develop and apply predictive models for distinguishing specific ETS factor binding patterns; (2) identify key transcriptional regulators of telomere- associated genes; (3) dissect the genome-wide co-localization and regulatory patterns of GABP and its cooperating factors; and, (4) develop and apply methods for predicting the transcriptional regulators of immune- checkpoint genes coordinated with telomere maintenance. The results of our research will establish a hitherto-unrecognized integration and coordination of mutant TERT promoter function, telomere maintenance, and immunotherapy resistance mediated through GABP and its interacting TFs.

NIH Research Projects · FY 2025 · 2011-08

PROJECT SUMMARY Phosphoinositides (PIPs) are minor components of the eukaryotic membrane but major regulators of cellular functions. The seven PIPs are critically involved in nearly every aspect of cell physiology. One of the cellular processes regulated by PIPs is autophagy, a process essential for a broad range of cellular functions and tissue development, and dysregulated in many human diseases. Found on late endosomes and lysosomes, PI(3,5)P2 is necessary for autophagosome maturation, and dysregulation of PI(3,5)P2 biogenesis has been linked to several neurological disorders through defective autophagy. However, the mechanism by which PI(3,5)P2 regulates autophagy is poorly understood. PIP signaling is often mediated by lipid-protein interactions. Our efforts in the last grant cycle have led to the development of a single-molecule assay that detects lipid interaction with proteins in mammalian whole-cell lysates, using which we have discovered widespread PIP interactions within the large family of human pleckstrin homology (PH) domain-containing proteins. XPLN, with dual activities as a RhoA guanine nucleotide exchange factor (GEF) and an endogenous inhibitor of mammalian target of rapamycin complex 2 (mTORC2), has emerged as a novel PI(3,5)P2-interacting protein, and we have also discovered that XPLN regulates autophagy in vivo. Guided by the working hypothesis that XPLN is an effector of PI(3,5)P2 and plays a central role in mediating PIP signaling in the regulation of autophagy, our proposed studies will decipher the biochemical basis of XPLN-PIP interactions and how they control XPLN activity and function. The role of XPLN phosphorylation by protein kinase C will also be investigated. We will ask how those biochemical mechanisms underlie the regulation of autophagy in mammalian cells. Finally, physiological relevance of the new mechanisms will be probed in a mouse model of injury-induced skeletal muscle regeneration, for which autophagy is required. Our expertise in lipid signaling, strong preliminary data, and a unique combination of biochemical, biophysical, cell biology, and animal model approaches will ensure a successful outcome that is likely to have significant impact on the biochemical and functional understanding of PIP signaling and regulation of autophagy.

NIH Research Projects · FY 2025 · 2010-05

PROJECT ABSTRACT Infrared (IR) spectroscopic imaging directly measures the chemical composition of cells and tissues for each pixel in the image. Using machine learning, this chemical data can be converted to pathology knowledge, without the use of dyes or stains – providing a potentially new avenue for clinical diagnoses and research to broadly aid public health. Since machine learning is integral to the approach, cognition of disease features can make diagnoses faster, cheaper and more precise. Interestingly, the approach can measure the tumor’s molecular characteristics and the microenvironment together in one shot. These capabilities can extend state of the art pathology practice by providing multiplexed stain-free molecular data and predictive models involving spatial and chemical information from multiple cell types. However, there are significant challenges and engineering development needed before this vision can be realized, including: (a) an imaging system that is competitive in measurement time with current clinical practice, (b) accurate and assured results that extend our ability beyond routine pathology, and (c) demonstration of robust use by pathologists and non-experts in technology. In the last project period(reported in 25 peer-reviewed publications, 2 granted patents), we developed “high-definition” (HD) IR imaging, which is now the standard commercial configuration for IR imaging manufacturers. We also developed the concept of “stainless staining” in which “low-definition” IR images appear to look like low-resolution stained images. We also demonstrated highly accurate breast tissue classification for a small number of pathologies. In this project period, we propose an advanced IR imaging system (newly designed optics, scanning) to make the technology powerful enough to provide a sample-to-image time of ~10 min for large surgical resections. This allows HD imaging in real time and will allow images, such as from stainless stains, be near the quality of those used by clinicians and researchers. Technological innovations lie in a design that is the first novel re-design of IR imaging in over 40 years and performance that is higher in speed, accuracy and image quality than ever before. Another critical part of our approach is to develop appropriate computational pipelinesfor extant problems in breast pathology. In addition to traditional models, we will validate the emerging tools of deep learning when appropriate. Finally, these technological realizations are followed by validation for a set of important problems in breast cancer care and research. The solutions will be rigorously evaluated against pathologist diagnoses, using high-quality, annotated data from 400 patients’ surgical resections and multiple tissue microarrays. Consequently, protocols for a number of identified pain points in breast pathology will result in addition to the technological progress, making the approach ready for use.

NIH Research Projects · FY 2025 · 2005-09

Project Summary The Summer Research Training Program at the College of Veterinary Medicine at the University of Illinois seeks to identify and facilitate the career progression of veterinary students who have the ability and motivation to become veterinarian medical scientists. The veterinary perspective has high value in biomedical research and there is a relative shortage of veterinarian scientists. Thus, the goals of this veterinary student training program are to help trainees understand the research process, gain research experience, learn scientific communication skills, and identify career opportunities and training pathways. The focus of this training program is translational biomedical research, broadly encompassing the research areas of infectious diseases, reproductive biology, epidemiology, neuroscience, oncology, toxicology, nutrition, and behavior. The productive and collaborative program faculty include 37 mentors from 11 different academic departments in five colleges. The 10-week program is open to veterinary students who have completed one or two years in the professional curriculum. A total of ten trainee positions are available each program year. Trainees are matched with a faculty mentor who shares similar research interests. In collaboration with the faculty mentor, trainees formulate a testable hypothesis, design the experiments, collect and analyze the experimental data, and report the conclusions. Reporting of results includes authoring an abstract that is submitted to a national meeting, preparing a poster presentation of the work, and writing a short manuscript formatted for a scientific journal appropriate for publishing the results. Extensive instruction in the Responsible Conduct of Research and Reproducibility and Rigor is provided through orientation week activities and a weekly seminar series. The seminar series also features presentations that highlight career opportunities available to veterinarian medical scientists, field trips to companies that hire veterinarian medical scientists, and an annual symposium with veterinary trainees and faculty from Purdue University. Scientific writing sessions are provided to assist trainees with preparation of the abstract, poster, and manuscript. At the conclusion of the program, trainees present their work at an in-house poster session and at the National Veterinary Scholars Symposium. Follow-up engagement over the course of the student’s DVM training and beyond provides support and mentoring to continue to develop research experience and the potential to pursue a veterinarian-scientist career.

NIH Research Projects · FY 2025 · 2004-08

The UIUC Neuroproteomics and Neurometabolomics Center on Cell-Cell Signaling develops innovative measurement and analysis tools and provides these tools to the NIDA research community. Rapidly evolving metabolomics, peptidomics, and proteomics methods facilitate new findings in both discovery and targeted modes. The Center provides high-end 'omics-scale characterization of the small molecules, peptides, and proteins in samples obtained from brain sub-regions like defined nuclei and even specific single cells. Our sampling methods facilitate molecular localization via high-throughput single cell isolation, mass spectrometry imaging, measurement of activity-dependent release, and quantitation of level changes as a function of exposure to drugs. We can then characterize the most important molecular targets in these samples using metabolomics, peptidomics, and proteomics (bottom-up, middle-down, top-down and protein complexes) via a broad array of mass spectrometry-based technologies. Finally, we provide the critical expertise for capturing the value of data via expert bioinformatics support that integrates disparate data types, develops advanced analytical approaches for complex metabolomics and proteomics experiments, and provides community support through several web platforms. At the beginning of the next project period, we will be supporting an initial group of 12 major users, representing the fields of addiction research and fundamental neuroscience with projects in cell-cell signaling, pain, pain management and pain mechanisms (especially as related to opioids), reward and motivation, unusual neurochemistry, and fundamental questions related to neuronal networks, memory, and behavior. The Neuroproteomics and Neurometabolomics Center on Cell-Cell Signaling is divided into three research cores: the Sampling and Separation Core, the Molecular Profiling and Characterization Core, and the Bioinformatics, Data Analytics and Predictive Modeling Core (plus an Administrative Core), and a Pilot Research Project Core. The Pilot Core invites new users to interact with our Center and includes an exemplary group of three initial pilot projects that includes a new investigator and a new research direction for an established investigator. The high level of synergy between the neuroscientists and technologists affiliated with the Center ensures we will enable exciting scientific advances in understanding how systems of neurons interact in both the healthy nervous system and upon exposure to drugs of abuse. Lastly, a series of outreach initiatives assures that our protocols and approaches are widely available to the appropriate scientific communities.