University Of Chicago

NIH Research Projects · FY 2025 · 2004-06

Abstract The dynamic regulation of metabolic states plays an active role in cellular differentiation decisions, and this occurs throughout mammalian development. The conservation of these processes in different species, developmental settings, and immune cell types suggests metabolism influences common mechanistic events needed for differentiation decisions in diverse cellular backgrounds. However, the interpretation of these conserved mechanisms must have a component of cell-type specificity to properly regulate the genome to promote appropriate differentiation in individual cellular settings. Therefore, it is important to define the conserved and cell-type specific mechanistic principles to understand how dietary and metabolic interventions influence immune cell differentiation in the context of healthy and disease states. In the previous funding cycle of this grant, we identified a role for alpha-ketoglutarate (aKG) in regulating the IL-2-sensitive gene program in T cells. Mechanistically, aKG-sensitive events enhanced the association of CTCF with a subset of sites in CD4+ T cells, and together with studies in cancer cells, the data indicated this overall activity is conserved in diverse cell-types. The data also suggested these events are interpreted in a cell-type specific manner, potentially based on the enhancer landscape of the cell. In this grant, we will extend these findings to address how aKG-sensitive CTCF sites are selected, and whether there are any cell-type dependent mechanisms selecting these sites. We will also define whether downstream mechanisms, such as enhancer activity, have sensitivity to metabolic states. In this context, we will address whether the enhancer landscape is regulated by short chain fatty acids such as butyrate and acetate. We will also define which aspects of metabolite-sensitive mechanisms are conserved between species, and how variation between the mouse and human genome influences the interpretation of conserved and cell-type specific events. Information gained in these studies will be critical for predicting the role for metabolic and dietary interventions in the treatment of immunological diseases and in promoting effective immune responses to infectious diseases.

NIH Research Projects · FY 2025 · 2002-09

Project Summary The overall goal of this project is to develop new statistical methods that address important problems in ge- nomics, to implement them in user-friendly open source software, and to make them available to scientists to facilitate new biological discoveries. To this end, the proposed work tackles three important problems arising in genomics where existing statistical methods are lacking, and where new, improved methods could accelerate the pace of scientific discovery: fine-mapping of functional traits; gene set enrichment analysis (GSEA); and discovering overlapping cluster structure in genomic data. The work on fine-mapping will enable the identification of genetic variants influencing common sequencing assays such as ATAC-seq and ChIP-seq, without pre-specifying the locations of potential effects. This unbiased approach will help identify regulatory genetic variants and interacting parts of the regulatory genome. The work on GSEA will provide a new more effective set of tools for researchers who use GSEA to set new findings in the context of known biology. The proposed work uses recently-developed statistical techniques to substantially reduce the redundancy of enriched gene sets, and will provide researchers with succinct and precise results that better highlight the full range of known biological factors that are relevant to a new set of findings. The work on overlapping cluster structure will provide new generally-applicable methods for understanding complex layered and hierarchical relationships that occur commonly in genomics applications (e.g. cell sub- types nested within cell types, layered on top of patient effects). The tools developed here will help scientists tackle a diverse range of analysis problems that arise in ge- nomics, ultimately helping them better understand the biology of disease, with the eventual goal of improving therapies and treatment strategies.

NIH Research Projects · FY 2026 · 2002-06

ABSTRACT Staphylococcus aureus is a human-adapted pathogen that replicates by asymptomatically colonizing its host. Nasal colonization is observed in the first weeks of life and persists despite the development of serum IgG against staphylococcal antigens. S. aureus is also an invasive pathogen, causing soft tissue, wound, lung, skeletal and bloodstream infections in community- and hospital-settings. Infection with antibiotic-resistant strains, designated methicillin-resistant S. aureus (MRSA), is associated with treatment failure and poor disease outcomes. MRSA and methicillin-sensitive (MSSA) strains are frequent causes of infectious disease morbidity and mortality in the United States. It is not always clear why colonization progresses to infection but such transition indicates that antibody responses elicited upon colonization are not protective. The surface of S. aureus is coated with over 10,000 molecules of Staphylococcal protein A (SpA) linked to peptidoglycan by the Sortase A enzyme. Using genetic and biochemical schemes, we found that peptidoglycan-modified SpA diverts antibodies away from their intended targets by interacting with the Fcg domain of IgG and by blocking complement activation. Thus, surface exposed SpA neutralizes the effector functions of pathogen-specific antibodies, including antibodies elicited by candidate vaccines. SpA is also released from the bacterial envelope and binds the variant heavy chains of VH3-IgM that serves as the B cell receptor (BCR) in approximately half of human B cells. SpA-BCR interactions prevent the development of neutralizing anti-SpA antibodies and instead trigger B cell proliferation and the secretion of VH3-rearranged antibodies with no specificity toward S. aureus. Carefully applied molecular engineering yielded the non-toxigenic SpA* vaccine that elicits SpA-neutralizing antibodies. When tested in our mouse model of colonization that takes advantage of the mouse-adapted strain WU1, we found that SpA* immunization leads to broad spectrum anti-S. aureus immune responses. We presume that some of these antibodies target the colonization factors of S. aureus that we seek to identify in this proposal. We also presume that during colonization SpA diffuses into nasal- associated lymphoid tissues to reprogram their B cell repertoire. Lastly, we will evaluate mechanisms of protection against colonization by examining the contribution of serum opsonophagocytic antibodies and luminal IgA for the nasopharyngeal clearance of S. aureus.

NIH Research Projects · FY 2026 · 2002-04

Abstract Protein kinases playing a critical role in cellular signaling represent an important class of anti-cancer targets pursued by the pharmaceutical industry. Nevertheless, designing highly specific kinase inhibitors and dealing with acquired drug resistance is challenging. Abl kinase inhibitors critical for the treatment of chronic myeloid leukemia (CML), provide a vivid illustration of many important concepts. When it was FDA approved in 2001, the drug imatinib (Gleevec) revolutionized the treatment of CML—converting for the first time a fatal cancer into a manageable condition. But drugging Abl by imatinib, a type II inhibitor that binds selectively to the inactive DFG- out conformational state of Abl kinase, faces major challenges due to the emergence of drug resistance mutations. Covalent drugs targeting specific residues represent a promising therapeutic route that can offer ways overcome drug resistance. But while there are now FDA-approved covalent kinase inhibitors, rationally designing covalent drugs is very difficult. The general philosophy is that poses where the warhead is in spatial proximity to a reactive amino acid are identified and used to construct a covalently bound adduct. But considerations based on spatial proximity in static binding poses are insufficient, and many mechanistic aspects of covalent binding remain poorly understood or overlooked. Progress is hindered by many fundamental questions that remain unanswered about the microscopic process of covalent inhibition. Owing to their growing significance, it is important to advance our understanding of covalent inhibitors and develop accurate computational treatments to support the rational design of these compounds. The overarching goal of this research proposal is to use computations and experiments to advance our fundamental comprehension of the key steps controlling the action of covalent kinase inhibitors, with a special focus on Abl kinase critical in the treatment of CML. The research is organized in four interrelated Specific Aims: (1) Development and application of multi-state kinetic scheme for modeling the covalent inhibition process together with a Bayesian Metropolis Monte Carlo (BMMC) procedure to serve as a “central hub” for analyzing, interpreting and integrating experimental measurements (time-course, dose-response, rate of inhibition) as well as computational results (classical and QM/MM simulations), (2) use classical MD simulations to characterize the dynamical flexibility of kinase substates identified by NMR, exploit novel Machine Learning strategies to establish a novel framework to simulate the reversible association/dissociation kinetics of inhibitors, and identify the factors affecting covalent engagement of bound inhibitors (linked and unlinked), and finally, use QM/MM simulations with the string method and advanced kinetic measurements to characterize the covalent inhibition of Abl kinase by novel class of lysine- targeting compounds developed in the Moellering lab from KW-2449 including (3) irreversible compounds with a sulfonyl-fluoride warhead, and (4) reversible compounds with an aldehyde warhead. Success in our proposed goals will expand our fundamental understanding of the process of covalent inhibition at the atomic level and will serve to establish a robust conceptual paradigm for the rational design of new kinase inhibitors.

NIH Research Projects · FY 2026 · 2002-03

ABSTRACT The concepts underlying the pathogenesis of type 1 diabetes (T1D) have seen a renaissance in recent years. Recently, there has been increased appreciation that β cells are an active, rather than passive, player in the disease process. A key recognition is that environmental insults in T1D (e.g. inflammation, virus) trigger molecular responses in β cells that potentiate detrimental communication with immune cells. In the next cycle of this R01 award, we propose to extend our work to link these cell-autonomous signaling pathways to their role in T1D pathogenesis. Our published and preliminary data demonstrate that a key inflammatory signaling pathway in β cells, the 12-lipoxygenase (12-LOX)/Gpr31 pathway, potentiates the integrated stress response (ISR). The integrated stress response (ISR) is a cytoprotective process whereby environmental stress signals such as proinflammatory cytokines, viral infections, and nutrient deprivation are transduced intracellularly to activate a host of eIF2α kinases. The phosphorylation of eIF2α halts general mRNA translation initiation in an effort to redirect energy expenditure to allay the prevailing stress. The blockade of this pathway though genetic or pharmacologic means suppresses the ISR, reduces β cell-immune cell crosstalk, and substantially diminishes T1D development in NOD mice. We hypothesize that inflammatory stress signaling within β cells exacerbates the ISR to both initiate and propagate autoimmunity in T1D. We propose the following 3 aims: Aim 1: Elucidate how 12-LOX/Gpr31 signaling links inflammatory signals to the ISR to drive T1D outcome. Aim 2: Determine how the β cell integrated stress response (ISR) promotes T1D susceptibility. Aim 3: Determine the mechanisms by which the 12-LOX/Gpr31 pathway and the ISR enhance cellular crosstalk between β cells and immune cells to promote autoimmunity in T1D. Whereas T1D is an autoimmune disease, therapies that have exclusively targeted the immune system have seen variable success. Recent clinical successes using drugs that block inflammation and stress pathways more broadly suggest a need to revise therapeutic approaches to T1D. Collectively, the work proposed in this application will harness the momentum behind β cell research in T1D to interrogate how stress signaling pathways influence crosstalk with the immune system to potentiate autoimmunity. We are competitively positioned with the relevant collaborative expertise and state-of-the-art, manipulable model systems across the translational spectrum from lower organisms to humans to test our underlying hypothesis and validate novel targets for T1D disease modification.

NIH Research Projects · FY 2025 · 2001-06

Project Summary Protein-protein interactions, self-assembly, and membrane targeting and remodeling are intimately associated with many critical cellular phenomena, including endocytosis, infection, immune response, organelle formation, cell division, signaling, and movement. These processes are innately multiscale, as they span from the molecular to nanoscopic to mesoscopic time and length scales. For instance, the molecular-level interactions between collections of proteins and the lipid membrane can have a profound effect on the large scale membrane morphology. Likewise, the atomistic details of actin and actin-binding protein interactions propagate to much longer length and time scales involving protein assembly processes in the cellular cytoskeleton. Therefore, the main scientific premise of this project is that it is critical to study, in a coupled fashion across multiple scales, the propagation of local molecular interactions upward in scale to the collective behavior at the cellular level. The research involves the continued development and application of novel multiscale, coarse-grained computational methods that are ideally suited to investigate the collective interactions of proteins with other proteins and with membranes, within the context of key cellular phenomena There are two main overarching aims of this research: (1) the continued development of new multiscale simulation methods that can be utilized to study increasingly complex aspects of large scale protein-protein and protein-mediated membrane processes, and (2) the elaboration of the mechanisms by which key proteins target and remodel realistic biological membranes, and how proteins interact and self-assemble with one another in the cytoskeleton and at the cytoskeleton-membrane interface. In collaboration with leading experimental researchers, the applications of the multiscale simulations will include studies of realistic membrane models, protein-mediated remodeling of membranes and actin filaments, the interaction of actin filaments with peripheral membrane proteins to regulate membrane curvature, and the mechanism of highly ordered coat protein-induced membrane remodeling. The overarching long term goal of this research is to continue to develop and apply a powerful and systematic multiscale computational approach for the study of realistic biomolecular phenomena of significant importance to various cellular phenomena.

NIH Research Projects · FY 2025 · 2001-02

1 We demonstrated in both mice and critically ill humans, that following surgical injury/infection, the gut 2 microbiota collapse in structure, membership and function (i.e., production of health-relevant metabolites) such 3 that both immune function and host recovery is impaired. In this proposal we seek to identify those metabolites 4 produced by the gut microbiota that play a key and causal role in determining the outcome from surgical 5 injury/infection via their ability to program macrophages such that they eliminate pathogens and resolve 6 inflammation with proper timing and coordination. We show, for the first time that gut microbiome-derived 7 metabolites (i.e., butyrate, indoles and others) can shift macrophages from the M1 to the M2 phenotype 8 leading to recovery from potentially lethal surgical infection (i.e., S. marcescens peritonitis). Work from our 9 collaborator (Lev Becker, PhD) recently described a “timer mechanism” by which key metabolites (i.e. lactate 10 and others) accumulate within macrophages, bind to histones and drive homeostatic gene expression so they 11 properly transition from M1 (pathogen elimination) to M2 (inflammation resolution). Therefore we will test the 12 hypothesis that recovery from surgical injury/infection is dependent on gut microbiome-generated 13 metabolites that program macrophages to clear pathogens and resolve inflammation in a properly 14 timed and regulated manner. Understanding the molecular details in this process will uncover a yet unknown 15 mechanism by which maintaining a healthy gut microbiome following surgical injury/infection enhances 16 survival. Therefore, in this proposal we will address the following specific aims: 17 Aim 1: Define the relationship between the gut microbiota, the metabolites it produces and their 18 effects on macrophage phenotypes that predicts recovery from surgical infection. 19 Aim2: Determine the composition of gut microbiome metabolites that activate macrophages co- 20 cultured with S. marcescens to express a survival-related phenotype and define the mechanisms 21 involved. 22 Aim 3: Enrich the mouse gut with select microbial consortia that are high producers of survival- 23 related gut metabolites and determine the mechanisms by which they enhance macrophage function 24 and survival following surgical injury/infection. 25 We are currently working with two world class experts in the field of immunology and microbiome sciences to 26 carry out the proposed studies and have already generated exciting and compelling preliminary data. These 27 include Dr Lev Becker, Associate Professor of Ben May Department of Cancer Research Committee on 28 Cancer Biology and the Committee on Molecular Metabolism and Nutrition and Dr Eric Pamer, Section of 29 Infectious Diseases and Global Health, Donald F. Steiner Professor; Director, The Duchossois Family Institute. 30 The work herein proposed is mechanistic, generalizable and highly translatable to surgical injury and infection.

NIH Research Projects · FY 2026 · 1999-05

PROJECT SUMMARY This proposal is a renewal application for R01 EY012549 entitled "Cell-Cell Signaling in Embryonic and Retinal Development". The question of how complex tissues like the eye achieve the cellular organization and three-dimensional form required for vision is of fundamental importance to understanding both normal developmental progression and disease mechanisms that perturb cell shapes, structures and patterns. A great deal is known about the genetically controlled terminal differentiation programs that produce the specialized cytoskeletal structures, cell-cell junctional adhesions and cell-extracellular matrix contacts unique to each retinal cell type. How the resulting cell shapes, structures and connections introduce physical constraints that influence final organ shape and function is not well-studied. This is particularly critical to a complex organ like the eye, because the organization of its diverse and highly specialized cell types must be precise to support vision. The goal of this proposal is to understand the cellular and tissue-scale properties and interactions that together sculpt the final form of the Drosophila compound eye. The fly retina provides a superbly tractable and well- defined experimental model, with a proven track record in uncovering conserved mechanisms. The stereotyped patterning and architecture of the fly retina facilitates the identification and tracking of individual cell types over space and time, and the wealth of available markers permits detailed analysis and quantification of cell shapes, structures, interactions and tissue-level patterns. Improving our understanding of fundamental morphogenetic processes has relevance not only to normal development and regenerative biology, but also to considering how disease-associated defects in one cell type or in one organ may influence adjacent cell types or organs. Thus, the knowledge gained from the studies described in this proposal will improve understanding of an important area of developmental biology and impact human health. Aim 1 will investigate how interactions between different retinal cell types elaborate and maintain the precise 3D tissue organization and structure required for vision. Our hypothesis is that cell-cell and cell-ecm interactions provide redundant mechanical coupling that organizes pattern, drives cellular differentiation and ensures robustness of the retinal morphogenetic program. Aim 2 will explore how tissue-intrinsic properties and the retinal-extrinsic environment contribute to the establishment and maintenance of retinal curvature, a tissue-level property critical for vision. We hypothesize that the pupal retina transitions from an initial “floppy” or viscous-like state that can be influenced by its physical environment to a rigid or elastic solid-like state that can autonomously support tissue shape.

NIH Research Projects · FY 2024 · 1998-07

PROJECT SUMMARY/ABSTRACT The University of Chicago is requesting continued support from the Agency for Healthcare Research and Quality (AHRQ) for the National Research Service Award (NRSA) program entitled the University of Chicago And Northwestern University Predoctoral Health Services Research Program (UCANU Predoctoral HSR Program), a joint predoctoral training program that began in 2013. The program will provide two to three years of support to outstanding candidates from participating predoctoral programs from both University of Chicago (UC) and Northwestern University (NU): Comparative Human Development (UC), Economics (UC), Psychology (UC), Sociology (UC), Public Health Sciences (UC), Business (UC), Public Policy (UC), Social Work (UC), and the Health Sciences Integrated Program (NU). The UCANU Predoctoral HSR Program draws upon the substantial and complementary resources, faculty, and expertise at both UC and NU to create new opportunities for our trainees to develop into productive health services researchers. This program links the well-established UC predoctoral training program that includes a strong disciplinary base with an eleven-year- old, interdisciplinary predoctoral program at NU. The UCANU Predoctoral HSR Program will continue to enhance the training provided by both programs by offering trainees a highly diverse group of peers and mentors, a joint UCANU seminar where trainees can present their research, formal coursework opportunities, and a wide array of settings in which to perform HSR. In this newest iteration, we will continue offering training in learning health systems research and enhance program activities to provide additional focused training in implementation science and promoting health equity. Overall, the UCANU Predoctoral HSR Program aims to produce the next generation of highly skilled health services researchers who will have the skills to conduct independent and collaborative research that will transform health care delivery and policy and advance health equity.

NIH Research Projects · FY 2026 · 1997-09

The mission of the University of Chicago Medicine Comprehensive Cancer Center (UCCCC) is to eradicate cancer through innovative and collaborative research, evidence-based prevention strategies, outstanding patient care, comprehensive education, and strong engagement with the communities we serve. Upon his arrival in March 2021 as Director, Kunle Odunsi, MD, PhD, articulated a vision for the Center that emphasizes advancing the translation of scientific discovery to improve cancer outcomes. To support this vision, UCCCC launched a Strategic Plan aimed at establishing the Center as a global leader in excellence across cancer care, research, and discovery—all in pursuit of eradicating cancer. The plan is organized around cross-cutting themes that include the bidirectional translation of cancer science across the laboratory, clinical, and patient care settings; the advancement of transdisciplinary research programs; and efforts to reduce the cancer burden within the catchment area and beyond. The 193 members of the UCCCC are organized into 4 Research Programs: Immunology and Cancer, Clinical and Experimental Therapeutics, Molecular Mechanisms of Cancer, and Cancer Prevention and Control. They are supported by 10 Shared Resources and 18 multidisciplinary Disease Teams. Notable accomplishments during the 2018–2022 funding cycle include: (1) Creating a new AD position focused on Shared Resources; (2) Recruiting 68 highly qualified researchers (45 new to the University of Chicago); (3) Expanding the Offices for Community Outreach and Engagement, Cancer Research Training and Education, Clinical Protocol and Data Management, and Protocol Review and Monitoring Systems; (4) Publishing 3,108 scientific articles 35% of which in high-impact (≥10) journals; (5) securing $55.4M peer-reviewed funding, with $31.0M from the NCI; (6) Achieving a 15% increase in accruals to interventional clinical trials, with 34% of enrollees from populations with limited access within the catchment area in calendar year 2022; and (7) Developing 51 new Investigator Initiated Trials (out of a total of 86 actively open), and 45 FDA INDs; (8) Launching several major initiatives including a unique scientific collaboration between UCCCC and Argonne National Laboratory. The Center is a full member of the National Comprehensive Cancer Network, Alliance for Clinical Trials in Oncology, the Children’s Oncology Group and participates in NRG Oncology studies as a LAPS main member. The aims of UCCCC in the next funding period are to: (1) Catalyze and conduct innovative, collaborative cancer research; (2) Accelerate the translation of UCCCC member discoveries; (3) Reduce cancer incidence and mortality in the catchment area by expanding access to prevention, diagnosis, and treatment strategies for patients across a range of demographic and clinical backgrounds; (4) Promote excellence in education, training, and mentorship; and (5) Foster a high-performing, collaborative research environment aligned with institutional values and operational excellence. Institutional commitment for the next funding period includes a $815M project to build a free-standing Cancer Pavilion.

NIH Research Projects · FY 2025 · 1996-12

PROJECT SUMMARY/ABSTRACT The main goal of the University of Chicago (UChicago) Digestive Diseases Research Core Center (DDRCC) for Interdisciplinary Study of Inflammatory Intestinal Disorders (C-IID) is to foster and facilitate interdisciplinary and innovative, patient-oriented, research in the field of complex inflammatory digestive diseases (DD), to understand and therapeutically exploit discoveries to improve the health of patients with DD. The UChicago C-IID is now in its 29th year, and, despite being a highly focused research program, has a multidisciplinary research base, with 46 full and 25 associate member investigators, and a total annual direct funding for DD that has increased by more than 40% since the last funding cycle, with $21.1 million of direct cost (not including funding from associate members). The ongoing CENTRAL HYPOTHESIS is that advances in care of patients with complex inflammatory diseases of the bowel requires a structure that empowers interdisciplinary clinical and discovery research investigating the mechanisms disrupting intestinal homeostasis and driving inflammation to identify therapeutic targets and foster translation of basic discoveries to development of new preventive and curative treatments. Taking-into-account the evolving scientific and technology advances and trends, and the interests of our members, we have re-aligned members around four C-IID cores that embrace four major interrelated research themes: Microbiome & Metabolism, Genetics, Genomics & Computation, Immune & Tissue response, and Translational & Clinical. Our OVERALL SPECIFIC AIMS are to: (i) build a highly collaborative, multidisciplinary team, (ii) identify and foster young investigators working in DD-related research, (iii) build a fully integrated translational research infrastructure with state-of-the-art core facilities and cutting-edge, high quality, and cost-effective services and resources, (iv) support a robust enrichment program, (v) promote interactions between the C-IID and other UChicago NIDDK centers and existing C-IID (especially with the Midwest DDRCC alliance). The C-IID has received tremendous institutional support as 1 of 5 priority areas designated for development by the Biological Sciences Division. The C-IID has successfully supported new investigators, but also drawn in talented scientists outside of the field of DD (8 now full members since 2015). Over the past two funding cycles, the P&F program has resulted in over $20.1M in extramural funds, or a 20 to 1 return- on-investment. Furthermore, 43% of the 322 publications acknowledging the C-IID for its support were coauthored by two or more C-IID members, indicating a high level of collaborative science. There was a 5-fold increase in the number of co-authored high impact papers (Impact factor>15) compared to the previous funding cycle. Thus, the C-IID has successfully met its goals of advancing the science and translation of discovery in inflammatory DD. The C-IID as a whole is greater than the sum of its parts. It provides strategic vision, cutting-edge, high quality, and cost-effective services and resources, and gives opportunity to current and next generation scientists to flourish in a highly collaborative and productive environment.

NIH Research Projects · FY 2026 · 1996-12

PROJECT SUMMARY – CENTER OVERVIEW The Chicago Diabetes Research and Training Center (DRTC) is a Chicago area Diabetes Research Center that is centered at the University of Chicago with the participation of investigators from the Northwestern University, the University of Illinois at Chicago, the Illinois Institute of Technology, and the Medical College of Wisconsin. Each institution has distinct scientific strengths yet shares a common interest in diabetes and related research. The DRTC includes 147 members, a growth of 20% in the last 5 years, with a total annual direct research funding of $124 million, of which $34 million comes from the NIDDK. The mission of the DRTC is to promote new discoveries and enhance scientific progress by supporting cutting-edge basic and clinical research on the etiology of diabetes and its complications with the goal of rapidly translating research findings into novel strategies for the diagnosis prevention, treatment and cure of diabetes and related conditions. To this end, we propose the following Aims: Aim 1. Create an intellectual and physical environment that supports important and innovative diabetes research. Aim 2. Raise awareness and interest in fundamental and clinical diabetes research in the greater Chicago area as well as nationally. Aim 3. Enhance diabetes research, education and training opportunities for patients, students, fellows, scientists and clinicians. Aim 4. Attract and retain early-stage investigators and investigators new to diabetes research; Aim 5. Provide high quality core services that leverage funding and unique expertise and serve the diabetes community locally, regionally and nationally. Aim 6. Connect researchers and foster interdisciplinary collaborations especially in emerging areas of research, to catalyze new ideas and scientific approaches. Aim 7. Promote the translation of scientific discoveries from the bench to bedside to community to improve public health. Aim 8. Participate actively in and contribute to the National Diabetes Research Center program. The DRTC will achieve these goals through the support of Biomedical Research Cores in Cell Biology, Physiology, and Genetics and Genomics (a Regional/National Resource), which provide cutting-edge and state- of-the-art services; through a Pilot & Feasibility Program to attract early stage investigators and investigators new to diabetes research; and through an Enrichment Program that promotes engagement, communication, and the exchange of ideas among patients, students, scientists and clinicians.

NIH Research Projects · FY 2025 · 1994-09

The University of Chicago (UC) proposes to continue the UC Specialized Training Program in the Demography and Economics of Aging program, that began in 1994, and requests funded trainee positions for 4 predoctoral fellows and 3 postdoctoral fellows per year. Housed in the interdisciplinary Center for Health and the Social Sciences (CHeSS), the NIA T32 Program draws upon the substantial and complementary resources, faculty, and expertise from across social science disciplines and related professional schools on UC’s campus, including the Social Science Division’s Departments of Economics, Sociology, and Comparative Human Development; the Biological Division’s Departments of Medicine and Public Health Sciences; the Harris School of Public Policy; the School of Social Service Administration; and the affiliated National Opinion Research Center (NORC). Our program’s record of trainee productivity and placement is excellent, as is the pool of trainees from which we select., As in past cycles, the program will continue to offer trainees a group of peers and mentors from a range of academic disciplines; an interdisciplinary Demography Workshop (DW) which brings both internal and external speakers to present aging-related demography research; a program-specific Postmortem Seminar, following the DW, that allows trainees in the program to discuss the presentation with their peers and faculty leaders; formal coursework opportunities in aging; and training in the Responsible Conduct of Research (RCR). This newest iteration will also enhance existing training opportunities through the expansion of the potential mentor pool, provide formal training in Methods to Enhance Reproducibility in Research and facilitate social survey methods training, increase the number of postdoctoral fellowship positions from 2 to 3 per year, and leverage the newly funded NIA P30 Center for Healthy Aging Behaviors and Longitudinal InvestigationS (CHABLIS) to increase training in longitudinal studies that examine how demographic and economic factors facilitate or suppress individual healthy aging behaviors across the life course. In addition, Kathleen Cagney, PhD, Professor of Sociology, who has served on the NIA T32 Committee on Demographic Training (CDT) Executive Committee (EC) for 12 years, will assume responsibilities as Program Director (PD) and Colm O’Muircheartaigh, PhD, Professor of Public Policy, will join the program leadership as Co-Director. Linda Waite, PhD, the George Hebert Mead Distinguished Service Professor of Sociology, who has served as PD of the program since its inception, will continue to be closely involved in the oversight of the program as a member of the CDT EC along with Dan Black, PhD, and David Meltzer, MD, PhD.

NIH Research Projects · FY 2025 · 1994-07

PROJECT SUMMARY The Cardiovascular Sciences Training Program (CSTP) at the University of Chicago provides both pre-doctoral and post-doctoral training. The postdoctoral trainees who participate in the CSTP include both M.D. and Ph.D. trainees. The M.D. trainees are physician scientists most commonly recruited from the Cardiology Fellowship Program at the University of Chicago, and the Ph.D. trainees have received their graduate degrees in diverse areas and seek additional training in the cardiovascular sciences. The CSTP also supports pre-doctoral training, an element essential to this integrated training program. The post-doctoral training strikes a balance between clinically-trained M.D. fellows who plan careers combining research with clinical medicine, and outstanding Ph.D. fellows who are dedicated to cardiovascular research. The CSTP offers training in six core components: 1) Molecular Cardiology and Cell Signaling 2) Genetics/Genomics of the Cardiovascular System 3) Development, Stem Cell Biology & Regeneration 4) Cardiovascular Imaging and Translational Biology 5) Vascular Biology & Inflammation 6) Systems Biology and Bioinformatics Each of these areas has as its scientific mission furthering our understanding of cardiovascular function in health and disease. To this end, participants in this training program receive didactic, laboratory-based, ethics, and analytic training in order to prepare for careers in cardiovascular research. We propose to continue supporting 3 pre-doctoral and 6 post-doctoral trainees. The range of experience for the post-doctoral trainees ranges from 0 to 6 years of post-doctoral training since M.D. fellows have often completed postgraduate medical training at the time they begin in full time research in the CSTP. In the last training period, we emphasized programs in genetic and genomics reflecting the growth in these fields and their successful application to the cardiovascular sciences. We also enriched training opportunities in regenerative sciences since important advances have been made for cardiac and vascular biology in this area. In this next interval, we have additionally enlisted trainers with accomplishments in systems biology and analysis responding to needs to take better advantage of emerging and existing “big data” and the expertise on the University of Chicago campus. Systems analysis will be integrated with cardiac genetics and development and regeneration biology, since these topics are critical to define the normal and abnormal function of the heart.

NIH Research Projects · FY 2026 · 1989-09

The Multi-disciplinary Training grant in Cancer Research (MTCR) is a pre-doctoral training program at the University of Chicago supported by NIH/NCI T32-009594 that trains our most talented pre-doctoral students to understand and target cancers using multi-disciplinary approaches. Pre-doctoral trainees are appointed to the MTCR T32 at the end of their first or second year in graduate school from feeder graduate programs, and are appointed for a minimum of one year, and usually reappointed for a second year, based on performance review of the past year in the program. Through stringent selection of faculty trainers, evolving coursework and training elements in translational cancer research, chemical biology, molecular engineering and computational approaches, the MTCR program provides opportunities that are multi-disciplinary and emphasize problem-based learning and hands-on experience. The MTCR also promotes effective career development through the MyCHOICE program and the Polsky Center for Entrepreneurship & Innovation where our trainees are exposed through seminars, workshops and internships to skills relevant to a career in biotechnology, science journalism and other research-intensive/related careers. In the past cycle, we have developed more effective mechanisms for trainee recruitment, through deployment of current trainees and our alumni network, in combination with more holistic rubrics for recruitment. As a result, our program has shown enhanced training outcomes in terms of publications, fellowship awards and percent trainees going into research-intensive and research-related careers, as well increased engagement of our trainees in the community, where our trainees have led many initiatives and also in biotechnology, where our trainees are now actively engaged in building collaborative research networks across the United States. Over the next 5 years with renewed funding, we aim to build on our successful approaches, while continuing to review and enhance existing training, for example through increased translational interactions as our new UChicago Cancer Pavilion (the first ever freestanding Cancer Center in Illinois) comes online in 2027, and with the new CZ Biohub Chicago. Our ultimate goal is to ensure that our pre-doctoral trainees, who are the next generation of cancer researchers, have the knowledge, skills and motivation to make a meaningful impact on the collective goal of minimizing cancer deaths in our time.

NIH Research Projects · FY 2025 · 1987-09

The objective of the University of Chicago Institutional T32 Training program is to provide a scientifically rigorous and intellectually stimulating interdisciplinary research training environment for physicians who have completed ACGME accredited residency training to prepare for research-intensive careers in academia, government and industry. Candidates for T32 training are nationally recruited through Residency Matching program to the Section of Hematology/Oncology within our Department of Medicine with the expectation that candidates for T32 training will complete one clinical year funded by the hospital and then have a minimum of two or three years of research training under the proposed training grant depending on whether they perform patient-oriented research or fundamental basic/translational/population research. The direction of the program – provision of multidisciplinary, structured, career development, mentoring and leadership opportunities in cancer research – has not changed since the program’s inception, but we have continued to evolve the program in response to a national need to develop and/or enhance research training opportunities for individuals interested in team science, translational research and patient-centric clinical trials to accelerate progress in cancer control and prevention. There are several unique structural elements in the research training proposed: 1) access to a large population of cancer patients in Chicagoland and Northern Indiana; 2) training under the guidance of multidisciplinary research preceptor(s) within a robust scientific environment that provides innovative scientific approaches, tools and technologies; 3) specific educational pathways in the form of course work and special seminars leading to advanced degree or certificate from any relevant unit in the University; and 4) community engagement and learning opportunities to accelerate progress in cancer care delivery science. The 33 Senior and 22 Clinical/Junior research training faculty preceptors have NIH or equivalent peer- reviewed funding, interact on several collaborative research and training efforts and are well qualified to serve as potential mentors for the six trainees per year participating in this T32 program. Our extensive inpatient and outpatient facilities across UChicago Medicine Network sites promote a comprehensive clinical training experience, while our research laboratories allow for the acquisition of basic research skills. With significant investments in new cancer programs and enhanced facilities, we have revamped our curriculum to offer coursework in emerging areas of cancer research including chemical biology, proteo-genomics, metabolomics, data science, and implementation science. Trainees have opportunities to participate in grant writing workshops, leadership development and entrepreneurship programs. With the rapid pace of scientific advances, preparing the next generation of highly competent, creative and compassionate physicians for research-intensive careers remains a wise investment for the nation. Physicians graduating from our training program are equipped to have sustained impact by conducting rigorous and reproducible research across the continuum of cancer care.

NIH Research Projects · FY 2025 · 1986-09

Project Summary Optimal allocation of attention is key to achieving peak behavioral performance. A detailed understanding of the neuronal mechanisms that control attention will be essential for any comprehensive strategies to reduce attention lapses or treat attention disorders. Moreover, better understanding of attention is likely to provide valuable new insights into sensory processing and perception. The visual system is an ideal subject for the study of attention. Peak visual performance is required for many human activities, and our relatively advanced understanding of the functional organization of the visual system makes it choice for deploying state-of-the-art techniques in well-described and well-differentiated brain regions. The experiments proposed here will advance our understanding of attention by providing a comprehensive characterization of the role of the locus coeruleus in visual attention. The locus coeruleus has long been associated with attention and arousal. However, the specificity of its contributions to attention has received relatively little investigation, despite many findings that suggest it has substantial functional specialization. Recent work in our lab has been directed at identifying distinct component of visual attention. We have shown that different brain structures make distinct contributions to changes in attention associated with behavioral sensitivity, selectivity, and perceptual criterion. Recently, we have used optogenetic stimulation of the locus coeruleus in monkeys and found that it can produce a robust and selective enhancement in behavioral sensitivity. This result emphasizes that the locus coeruleus is a potent factor in controlling visual attention, and highlights how little we know about the role it plays in controlling the various components that make up visual attention. We will optogenetically activate locus coeruleus neurons to measure their influence on visual sensitivity, selectivity and perceptual criterion, measuring both the magnitude and the dynamics of attention-related behavioral enhancements that it mediates. To reveal how it enhances visual performance, we will record visual responses from key visual structures – area V4, the frontal eye fields and the superior colliculus – during locus coeruleus stimulation to directly assess how it contributes to the quality of central representations of behaviorally- relevant visual stimuli. We will also record neuronal responses from the locus coeruleus itself while monkeys do tasks that modulate specific components of visual attention. The results from these recordings will provide a direct, detailed appraisal of the extent of specialization that exists within the locus coeruleus. The locus coeruleus plays a major role in behavioral performance, yet its role has been largely overlooked in efforts to understand the neurophysiology of visual attention. The proposed experiments will provide a precise, comprehensive assessment of the place of the locus coeruleus in attention and will substantially advance our understanding of the interaction of different brain structures in mediating visual behaviors.

NIH Research Projects · FY 2025 · 1985-08

The objective of our competing renewal application for the University of Chicago Research Training Program in Respiratory Biology is to prepare young scientists and physician scientists to pursue research careers addressing mechanisms and treatment of human disease, with a focus on respiratory pathobiology. The cohesiveness of this interdisciplinary Program stems from the highly collaborative nature of our 45 well-funded faculty from 9 departments across the University of Chicago, who together address the four respiratory disease domains – Airways Disease; Interstitial Lung Disease and Lung Transplantation; Critical Illness (including Acute Lung Injury); and Sleep and Hypoxia – employing a range of modern research approaches that center on Immunology, Physiology, and Microbiome; Genetics and Epigenetics; Data Science, Machine Learning, and Artificial Intelligence; Clinical Outcomes; Healthcare Delivery; and Ethics and Implementation. The Program Directors are Gokhan M. Mutlu, MD and Yun Fang, PhD, with Associate Directors Valerie Press, MD (Mentorship and Career Development) and Julian Solway, MD. Internal and External Advisors provide oversight and continuity of review, and an Admissions/Steering Committee oversee trainee admissions and reviews trainee progress. We request funding for 8 post-doctoral trainees. PhD, MD, and MD/PhD trainees are enrolled and trained together. Collaboration of basic and clinical scientists on research further enhances the integrative and translational nature of our program. All MD fellows will perform full-time research for at least 2 years, and will devote not more than 10% time to clinical training while supported by this Training Program. Training consists of 5 major components: a Research Project performed under the direct supervision of faculty co-mentors; a Core Curriculum of robust seminar series and courses with additional, tailored formal coursework; Core Competencies that includes scientific communication, grant writing, mentoring, and responsible, rigorous, and reproducible conduct of research; Multidisciplinary Research; and Individualized Career Development Planning. Prior trainees from this Training Program have developed successful independent research careers in large proportion. Refinements presented here should further enhance the likelihood of success of future trainees.

NIH Research Projects · FY 2025 · 1981-08

Voltage sensing is found in many in biological processes and it is fundamental in excitable tissues. This project aims at understanding the physical bases of voltage sensing and how it acts on channel opening at the molecular level. We propose to find the structural basis of function with the following aims: AIM1. Understanding the voltage sensor domain (VSD)-PORE energy landscape with time-dependent temperature jumps. We have developed a method that allows for fast and homogeneous increase in temperature in the area from which function (gating and ionic currents) and the T are measured. We will explore the energy landscape of the Shaker K channel VSD-pore by applying T jumps at different times and voltages during the development of the gating currents and by modifying the landscape with mutations that stabilize intermediate states, which differentially affects a population of particular states in the energy landscape. The results will be interpreted using a structure- based Brownian motion model of the sensor, which correlates the landscape energetic features with the VSD structure and the physical parameters of the sensor and its medium. AIM 2. The coupling between sensor and pore domains. Our previous findings of non-canonical coupling in Shaker is a guide to explore its relevance and function in other channels. 2a. We will study noncanonical VSD-pore coupling in Nav1.4 sodium channel, guided by the structures and the Shaker results by mutation of residues that may couple the four surfaces to the pore using gating and ionic currents while searching for the origin of interdomain cooperativity. 2b. In BK, a non- domain-swapped channel, we hypothesize that the voltage sensor move only two arginines across a fraction of the field based on our preliminary data. To test the hypothesis we will replace arginines with histidines and look for pores or transporters. The arginine trajectories will be inferred by replaced them by qBBR, a positively charged fluorescent probe that is quenched by tryptophan and tyrosine in their path, as we did with Shaker. We will test with mutations and CryoEM structures a noncanonical coupling of S4 via S5 that may gate the channel either by acting on the selectivity filter or directly on an S6 rotation inducing dewetting. 3. VSD-Pore coupling and Inactivation of the Sodium channel. CryoEM structures give no clear mechanistic understanding of Na channel inactivation. We hypothesize that a docked IFM is not the inactivating particle but triggers inactivation. We will first define the inactivation gate, that we propose is made by bulky hydrophobic residues in S6 segments that rotate into position to obstruct conduction, based on our preliminary data where residues impair inactivation when their volume are decreased, with possible inactivation gate restoration by methylsulfonate conjugation when those residues are replaced by cysteine. The linker connecting the IFM motif receptor to the inactivation is a postulated chain of residues that will be studied by mutational and CryoEM structural analysis. This research is expected to uncover voltage sensing and pore coupling structural basis applied to understanding of pathological conditions such as epilepsy or myotonias.

NIH Research Projects · FY 2026 · 1979-07

PROJECT SUMMARY The broad objective of this research proposal is to advance our understanding of thyroid physiology through the study of genetic defects at key regulatory processes. In addition to identification of new syndromes and gene defects, research centers on regulation of gene expression and gene therapy. The program owes its success to the worldwide referral of patient material, to the clinical and technical skills of the PI’s laboratory, and to collaborative arrangements with accomplished investigators from the US and abroad that provide complementary knowledge and technical expertise. The proposal by multiple PIs for continuing funding encompasses three aims. (1) Determine the mechanism by which several newly identified genetic defects produce the observed thyroid phenotypes. These include the selenoenzyme deiodinases D1 and D3; PKHD1L1 mutations by studying the Pkdh1l1KO mice; and LRP2 mutations by in vitro structural and functional characterization. (2) Determine the mechanism of resistance to TSH (RTSH) caused by mutations in a primate- specific short tandem repeat (STR) on chromosome-15. Human thyroid organoids recently developed in collaboration will be used to generate STR mutant thyroid organoids using CRISPR/Cas9 or PiggyBac transposon as a genome editing tool, in order to study the physiological function of this primate specific STR and its role in the dominantly inherited phenotype of RTSH. TSH sensitivity of normal and mutant organoids will be determined in vitro or in vivo after transplantation into hypothyroid mice. (3) Determine the effectiveness of combined gene and thyroid hormone (TH) analogue treatments in monocarboxylate 8 (MCT8) deficiency. The X chromosome linked MCT8 deficiency produces in boys a disease known as Allan-Herndon-Dudley-Syndrome (AHDS) with severe neuropsychomotor defects, caused by deficiency of TH transport in brain, and systemic thyrotoxicosis caused by excess of circulating T3. Double knockout (dKO) mice, lacking Mct8 and the TH transporter Oatp1c1, recapitulate the findings of AHDS. We recently showed that gene therapy in peripubertal dKO mice with adeno associated virus 9 (AAV9) containing the human MCT8 cDNA improved the locomotor and cognitive function by near normalization of brain T3 content but failed to correct the serum thyroid tests. We propose to add the TH analogues diiodothyropropionic acid (DITPA) or triiodothyroacetic acid (TRIAC) that are known to correct the thyrotoxicosis of AHDS in peripheral tissues but not the neuropsychomotor manifestations, to achieve rescue of this incapacitating disease. The proposed research will result in the discovery of new genes and mechanisms causing congenital and inherited thyroid diseases. In addition to knowledge gained regarding thyroid physiology and pathophysiology, these studies will provide the means for rapid and specific diagnosis and for rationale of innovative treatments.

NIH Research Projects · FY 2025 · 1979-07

PROJECT SUMMARY: The Interdisciplinary Training Program in Immunology (ITPI), currently in its 45th year, represents the primary support for graduate students in Immunology at the University of Chicago. The program is embodied by the Committee on Immunology, an interdisciplinary and interdepartmental academic unit that serves as the scientific community for immunology graduate students, postdocs, and faculty at the University. The ITPI supports eight training slots and features 34 distinguished faculty selected for their outstanding research and training records, their well-funded laboratories, and their dynamic involvement in all aspects of graduate education. Their research spans a broad spectrum of modern areas of immunology including cellular and molecular immunology, biochemistry, genomics, and microbiome studies, with a proven record of interdisciplinary collaborations. New strength stems from the recent implementation of the Computational & Systems Immunology (CSI) specialty track for Immunology trainees seeking the advanced conceptual and technical training needed to tackle immunological questions using quantitative and systems-level genomic approaches. This initiative is buoyed by our recent recruitment of eight junior faculty who are emerging leaders in three priority areas, including CSI, human immunology, and molecular engineering, as well as the development of two new specialized graduate courses in data sciences tailored specifically for Immunology trainees. All students in the ITPI receive advanced training through courses focused on the critical analysis of primary literature and experimental design, with special emphasis on bioinformatics skills, rigor and reproducibility, and the responsible conduct of research. The comprehensive training includes a weekly Seminar Series, Work-in-Progress forum, and Journal Club, as well as unique scientific events such as the Joint Immunology Retreat and the T32 Career Perspectives in Immunology virtual event, which both stem from a joint partnership with Washington University in St. Louis. Career development is enhanced through MyChoice, an institutional program enabling trainees to further develop academic skills and gain exposure to a broad array of research-intensive career paths. The Biological Sciences Division provides strong institutional support, as shown by sustained financial and administrative support, the operation of cutting-edge core facilities, and the implementation of major initiatives such as the Duchossois Family Institute, which aims to harness the power of the microbiome and immunity for human health. The ITPI is continuously and rigorously evaluated with respect to organization, process, objectives, and outcomes. This is one of the most outstanding and competitive training programs in the country, as shown by the high retention and completion rates of our trainees, their impressive publication record (average of five publications per trainee, including many first-author publications in high-impact journals (IF>20), and their success in securing independent careers in research-intensive and research-related areas.

NIH Research Projects · FY 2025 · 1978-07

PROJECT SUMMARY/ABSTRACT This NIH T32 postdoctoral training program in Clinical Therapeutics at the University of Chicago (UC) represents a diverse, nurturing, and scientifically stimulating environment whose educational purpose is the advanced research training of clinicians and translational scientists in clinical pharmacology, pharmacogenomics and therapeutics, with a goal of sustaining and expanding the future workforce within these important fields. Accredited by the American Board of Clinical Pharmacology, our training program operates within the rigorous educational and research climate of the UC Committee on Clinical Pharmacology and Pharmacogenomics (CCPP), a formal interdepartmental academic unit responsible for the administration of the training program and housing its research and training faculty. Peter H. O’Donnell, MD, CCPP Chair, directs the program along with Mark J. Ratain, MD. The multi-PD/PIs are assisted in program leadership by an Executive Committee, a Fellowship Recruitment and Selection Committee, an Education Committee, and an External Advisory Committee. Within UC, the program fulfills an exclusive niche, providing focused training to individuals having a clinical background (MDs, MD/PhDs, PharmDs, PharmD/PhDs, or select PhDs with a clinical focus). Many trainees enter the program while also pursuing subspecialty clinical fellowship training. This opportunity for dual fellowship training within a chosen subspecialty clinical area combined with clinical pharmacology creates a foundational research expertise that promotes the development of impactful scientific contributions within the realm of clinical therapeutics. Our fellowship program provides primary protected research time for advanced training in a chosen research area, structured as a mentored, hypothesis-driven two-year arc designed by the trainee and their mentor(s) and approved by the Executive Committee. This is supplemented by formal programmatic didactic coursework, experiential learning rotations, teaching opportunities, and clinical exposure in personalized therapeutics through a required rotation in the UC Personalized Therapeutics Clinic. Although the primary mission is to prepare clinicians for an academic research career, the program also has successfully trained scientists for prominent careers in government and industry. Upon completion of the program, graduates are accomplished in basic research methodology, experimental design, and data interpretation and presentation, and are uniquely prepared for a competitive research career in clinical therapeutics, as well as certification in Clinical Pharmacology.

NIH Research Projects · FY 2024 · 1978-02

The long-term objective is to use animal models to find mechanisms and approaches whereby adoptively transferred T cells transduced with mutant neoantigen-specific TCRs can eradicate solid cancers in patients without destroying normal tissues. Tumors in patients have been present at least for months or years and are usually at least 1cm in diameter at time of diagnosis. Therefore, large and long-established solid tumors expressing autochthonous (untransfected) mutant neoantigens are the focus of this proposal. A key element being explored is the destruction of the immunosuppressive stromal tumor microenvironment by transfer of MHC Class II restricted neoantigen-specific TCR-transduced CD4+ T cells (CD4+TCR). These T cells cause tumor destruction followed by long-term arrest of tumor growth. A second key element being explored is that CD4+TCR T cells form 4-cell-type clusters with MHC Class I restricted neoantigen-specific TCR-transduced CD8+ T cells (CD8+TCR) which are attracted to the cluster by recognizing the cross-presented neoantigen on stromal CD11b+ tumor-associated macrophages. Finally, intraclonal non-heritable heterogeneity is explored as novel mechanism of escape of cancers despite cancer cells seemingly lacking mutant neoantigen-negative variants. Aim 1 is to determine the requirements and mechanisms for CD4+TCR T cells to destroy, without CD8+ T cells, advanced solid tumors and subsequently arrest their growth. It will be tested whether targeting tumor stroma is essential for this CD4+TCR-mediated destruction/arrest and whether these effects are independent of direct cancer cell recognition. Furthermore, it will be examined whether therapeutic CD4+TCRs can be isolated from tumor-infiltrating lymphocytes (TILs) that are failing to reject the cancer. Finally, it will be tested whether appropriate lysosomal processing of mutant neoantigen is a decisive predictor for CD4+TCR- mediated tumor destruction. Aim 2 is to determine whether 4-cell-type clusters at the effector phase are essential for cancer eradication by CD4+TCRs and CD8+TCRs. It will be analyzed whether direct cancer cell recognition by the CD8+TCR is required for cancer eradication. Furthermore, it will be tested whether, for synergistic cancer cell destruction, the two neoantigens must be released from the same cancer cell because this would allow the CD8+TCR T cells to recognize the cross-presented neoantigen on the same CD11b+ stromal cell also being recognized by the CD4+TCR T cells. Antigen-specific 4-cell-type cluster formation will be quantified and modeled in vitro using longitudinal time-lapse imaging. Finally, will be determined whether cancers brought into equilibrium by CD4+TCRs can still be eradicated by subsequent treatment with CD8+TCR transduced T cells. Aim 3 is to determine mechanisms of escape and the molecular nature of CD8+TCR recognized antigens that can be used to eradicate cancers in synergy with CD4+TCRs. It will be examined whether cloned cancer cells seemingly lacking antigen-negative variants nevertheless escape by the presence of cancer cells with low mutant mRNA expression due to intraclonal heterogeneity.

NIH Research Projects · FY 2025 · 1975-07

The overall goal of the Integrated Clinical and Basic Endocrinology Research Training Program (ERTP) is to train capable, creative, and thoughtful adult and pediatric endocrinologists for careers in modern endocrine investigation. At the completion of training, it is anticipated that trainees will be able to independently initiate investigations into areas important for understanding of endocrine disorders or of health disparities and economics in populations with endocrine disorders.

NIH Research Projects · FY 2025 · 1975-07

Project Summary The University of Chicago Growth, Development and Disabilities MD/PhD Training Program is designed to provide basic science and translational research training for a highly selective group of medical students in a combined-degree program. The Program is based on the premise that a commitment to complete both the MD and PhD degrees and to establish and maintain a research-focused career is only developed after some time in medical school (hence no attrition from this training program since 1978). Students are chosen on the basis of outstanding academic credentials, demonstrated ability in basic science, and devotion to pursuit of a research-oriented career. All students fulfill the requirements of a PhD in a particular discipline and complete the same requirements for the MD as other medical students. They are continuously and longitudinally advised by the Program Director, co-Directors and staff, a Student Advisory Committee, an External Advisory Committee, and Mentors who have outstanding records of promoting the training, education and career advancement of biomedical scientists. The Program attempts to closely align its training goals with the mission of NICHD to foster training in the areas of growth, development, and disabilities research and clinical specialties in pediatrics and related areas. The overall Program, its elements, and the participants are assessed via multiple evaluation tools through the year. The ultimate success is measured by the impact of the trainees’ thesis research, the completion of both the MD and PhD degrees, and their long-term success as physician-scientists.