University Of Chicago

NIH Research Projects · FY 2025 · 2019-06

With the increasing complexity of cancer care, the rising numbers of cancer survivors in the US population, and the increasing global burden of cancer, it is critical that Pritzker School of Medicine (PSOM), one of the most research-intensive medical schools, prepare a workforce trained to meet these challenges. While the workforce for the continuum of cancer care is interdisciplinary and inter-professional, to date, medical education has remained compartmentalized. In our first funding period, we have revised our medical school curriculum and transformed our approach to training medical students at PSOM via the Scholars in Oncology Associated Research (SOAR) program. In a highly innovative 10-week intensive summer program, SOAR successfully enrolled 63 participants (51 NCI funded, 12 PSOM funded). The SOAR program successfully inspired nearly 70% of participants to continue their cancer research, leading to 52 cancer-related conference presentations and 37 cancer-related publications. SOAR participants had higher research self-efficacy and intent to enter a research career than non-SOAR peers and a deepening of their commitment to cancer research. We propose to continue SOAR to enroll 12 medical students each year, including 4 who will conduct global cancer research at UChicago Global partner sites in compliance with the US State Department and NIH/NCI policies. Each student will conduct interdisciplinary cutting-edge cancer research with strong mentorship by established investigators in the University of Chicago Comprehensive Cancer Center or the Susan and Richard Kiphart Family Center for Global Health. In addition, trainees will take part in formal instruction in responsible conduct of research, didactic lectures on the science of oncology, interdisciplinary tumor boards, journal clubs, research skill development and career planning activities as well as opportunities for career exploration, networking, and outreach that will increase their knowledge of cancer and motivate them to pursue further education and training for future careers as cancer researchers. Trainees will be supported by a tiered mentorship structure that includes Faculty Track Group Leaders who will be responsible for monitoring progress along milestones of completing their projects and lead peer mentoring sessions where they learn about each other’s research. Using didactic sessions, experiential research training in settings that represent the cancer care continuum from prevention to survivorship, and exposure to national and global leaders in oncology research, SOAR participants will have a greater appreciation for the interdisciplinary and interprofessional nature of oncology care and research. With rigorous evaluation and planning, we will continue to build on our success with SOAR and determine if SOAR participants show a greater propensity to enter cancer research/oncology careers, while tracking outcomes such as publications, grants, and entry into academic careers. SOAR will enable PSOM to maintain its tradition of excellence in preparing a highly skilled workforce to achieve the promise of precision oncology care and reduce global disparities in cancer outcomes.

NIH Research Projects · FY 2025 · 2019-06

Effective response to the overdose crisis requires rigorously conducted scientific investigations, with a specific focus on criminal legal system, to identify interventions, strategies and approaches that are efficient, feasible, scalable, and sustainable. Phase I of the Justice Community Overdose Innovation Network (JCOIN) created under the NIDA HEAL initiative funded a series of investigations targeting key stages of the substance use treatment continuum as people with substance use disorders interact with the criminal legal system. Together with the new research hubs that will be identified during JCOIN Phase II, these studies will generate a large amount of rich data from the most vulnerable populations in the U.S. opening opportunities for analyses beyond the primary study aims to maximize the impact of investment into scientific research – one of the primary foci of the Methodology and Advanced Analytics Resource Center (MAARC). The MAARC will also provide overall leadership and coordination of centralized data management; data infrastructure support; provide resources for advanced analytical techniques across the network; research dynamic changes in policy and practice in criminal-legal/community service settings; and conduct novel studies applying cutting edge analytical techniques to existing data and data collected across the JCOIN network: Aim 1. The Administrative Core will Integrate existing organizational and collaborative infrastructure to provide overarching resources and organizational structure and management to the Center; Aim 2. The Data and Analytics Support Core will continue to facilitate the collection, archiving, and storage of data collected by the Research Hubs, assist with closeout and curation of Phase 1 data and facilitate internal and external data sharing across both JCOIN Phases; Aim 3. The Technical Assistance Core will support on-demand technical assistance (consultation) and provide appropriate resources to JCOIN Phase I PIs, JCOIN Phase II researchers, and scientists across NIDA and beyond; Aim 4. The Survey Core will leverage NORC’s expertise to support national surveys about topics broadly relevant to substance use, stigma, behavioral health, criminal-legal systems, and public health with opportunities for specialized surveys of Criminal Justice systems as well as modified referral sampling of AmeriSpeak adjacent community members; Aim 5. The Geospatial Core will build upon popular geospatial tools, data and policy scans from Phase 1 to support innovative geospatial analysis that address important gaps in the environmental context of overdoses in criminal legal involved community members; Aim 6. The Modeling Core will develop an agent-based network modeling framework to conduct experiments of JCOIN trials and other in-silico trials guided by JCOIN investigators and other practitioners using multiple existing and new data sources; Aim 7. The Policy Landscape Core will inventory and characterize major policy/legal environmental changes with specific focus on Medicaid at the state and national level and produce datasets and related resources that can be used by JCOIN researchers and the larger NIDA research community. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.

NIH Research Projects · FY 2026 · 2019-06

Abstract: Understanding the genetic basis of gene regulation is key to understanding the evolutionary processes that have shaped specific traits in humans and non-human apes. In turn, identifying and characterizing the genetic variants that lead to inter-individual responses to different exposures is critical to gain insight into gene by environment interactions and associated phenotypic consequences. By elucidating the genetic variation that underlies regulatory differences between species, and the genetic variation that is associated with individual differences in response to environmental cues, we can gain a better understanding of the evolutionary processes that led to human-specific traits, as well as the genetic basis of complex traits and diseases. The challenge is that to carry out this work in humans and other apes, one must rely on in vitro systems. During the first term of the MIRA award, my lab focused on understanding the molecular mechanisms that underlie the evolution of gene expression, such as natural selection, the influence of epigenetic marks, and the effects of gene duplication. We developed and broadly shared a comparative panel of iPSCs from humans and chimpanzees, and we established a new approach for iPSC differentiation (we call it ‘guided differentiation’), which makes it feasible for us to study gene regulation across a broad range of cell types and contexts. We used these systems to study the impact of variation in gene regulatory networks on complex diseases and the role of gene regulation in the generation of phenotypic diversity. We explored the roles of gene expression in human diseases, such as cancer and neurological disorders, and developed methods for analyzing comparative single-cell gene expression data. In the next term of this award, we propose to continue to study similar broad areas. We will sharpen our focus on gene by environment interactions and develop a better understanding of the genetic variation that leads to regulatory variation in response to different exposures. We will employ a dynamic eQTL mapping approach to offer additional insight into the genetic basis for disease. We will also explore the role of epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, in mediating gene by environment interactions. We will use the comparative iPSC panel to explore the relative impact and evolutionary consequences of changes in cis and trans regulatory mechanisms in dozens of different tissues and cell types and continue to share the panel and derivative cultures with the community. Finally, we will take advantage of improved single-cell technologies to characterize the dispersion and robustness associated with single-cell gene regulation and identify genetic mechanisms that underlie the regulation of gene regulatory noise.

NIH Research Projects · FY 2026 · 2019-03

PROJECT SUMMARY This application supports the participation of the University of the Chicago Medicine Comprehensive Cancer Center (UCCCC) as a Lead Academic Participating Site (LAPS) in the National Clinical Trials Network (NCTN). The NCTN develops and performs state-of-the-art early and late stage clinical trials for the treatment of adults with cancer. UCCCC has been a long-standing member of the Alliance for Clinical Trials in Oncology and NRG Oncology, and of the cooperative groups that preceded the formation of the NCTN. The UCCCC will provide multi-disciplinary scientific and administrative leadership in the design of innovative and potentially practice- changing clinical trials within the NCTN. UCCCC faculty members will contribute to the NCTN as operational leaders, committee chairs, committee vice-chairs, committee leaders, and study chairs, and as members of NCI Advisory and Scientific Committees. Preliminary studies performed by UCCCC investigators at the University of Chicago will be brought to the NCTN for large scale testing. Laboratories at the University of Chicago will perform correlative studies that will support NCTN trials. University of Chicago senior faculty will mentor young investigators to become future leaders in the NCTN. The UCCCC has the infrastructure for the initiation and conduct of a wide spectrum of clinical trials, supported through the Clinical Trials Support Office (CTSO), the primary component of the Clinical Protocol and Data Management (CPDM) unit of the Cancer Center Support Grant, which manages the regulatory activities for all adult cancer-related clinical trials. NCTN LAPS activities at UCCCC will be coordinated by a Steering Committee, comprised of 4 Principal Investigators who represent medical, radiation, gynecologic/surgical and translational oncology, and 3 senior administrative leaders in the UCCCC. The Steering Committee will oversee the NCTN Coordinating Center in the Clinical Trials Support Office, which will provide centralized regulatory oversight and data quality control support for the implementation, quality execution of, and efficient accrual to, NCTN trials across the Network. UCCCC will collaborate with the Network Group Operations Centers and the associated Network Group Statistics and Data Management Centers to achieve the research goals of the NCTN program. The UCCCC will thus provide a mechanism for robust accrual to trials across the NCTN, with participation across all tumor types, including trials for rare cancers and in a diverse patient population, at the UCCCC main campus in Hyde Park, at five Integral Component Network Sites, and at 1 LAPS Affiliate Site.

NIH Research Projects · FY 2025 · 2018-09

PROJECT SUMMARY Our goal is to discover how closely related species adopted unrelated axis determinants for specifying the anterior embryo. Many aspects of animal development are conserved between species as different as humans and flies, but some key regulators change very rapidly over the course of evolution for unknown reasons. Explaining such unexpected plasticity in developmental gene networks will help us understand the basic science of developmental robustness and congenital disease in all animals, including humans. Comparing multiple closely related species is a powerful approach for understanding causes of plasticity in gene networks. This approach is extremely difficult to implement with vertebrate model organisms but can be readily accomplished in insects. Flies (Diptera) are particularly suitable because they include Drosophila melanogaster, one of the leading model organisms in developmental biology, and because other dipteran species that can be cultured in a laboratory setting are amenable to functional studies. Our research in a variety of dipteran model organisms during the previous funding period established that these closely related species use a broad range of anterior determinants (ADs) for establishing embryo polarity and anterior-specific gene expression, most likely through the formation of long-range transcription factor gradients with morphogen-like activity. This discovery enables us to examine why key developmental regulators can be highly unstable in evolution. While Drosophila’s AD (Bicoid) is a classic morphogen model, it is not known whether its mechanism of action can be generalized nor how the evolutionary transition to Bicoid-dependent pattern formation was achieved. The first of these two questions will be addressed by identifying and characterizing chromatin and gene targets of the AD in the moth fly Clogmia albipunctata, Cal-Opamat (Aim 1) and of the AD in the common midge Chironomus riparius, Panish (Aim 2). This will be done by testing for AD-dependent chromatin accessibility in stage-matched embryos with or without reduced AD activity, using ATAC-seq and RNAi. These experiments will be complemented as needed by ChIP-seq, and by characterizing the expression and function of predicted target genes in vivo. The second question, concerning the transition to Bicoid- dependent pattern formation, will be addressed by determining the mechanism of anterior specification in the soldier fly Hermetia illucens (Aim 3). This organism was chosen because it is the closest tractable outgroup to the clade of species with bicoid. A pilot study revealed several AD candidates, including Hil-Stau, the ortholog of Staufen. This RNA-binding protein binds bicoid mRNA in early Drosophila embryos. To identify Hermetia’s AD, anterior-localized and Hil-Stau-binding mRNAs will be determined by expression studies, co- immunoprecipitation, sequencing, and their function will be examined by RNAi. The determination of the anterior- specification mechanisms of Clogmia, Chironomus, and Hermetia will result in a new framework for explaining evolutionary plasticity of a key regulator in a classic model for pattern formation and gene regulation.

NIH Research Projects · FY 2026 · 2018-09

Diabetes is traditionally classified in two broad categories: autoimmune Type 1 and obesity-related Type 2. Numerous phenotypically and etiologically distinct forms exist and are emerging, collectively termed “atypical diabetes”, that do not fit into either category. We hypothesize that atypical diabetes comprises a spectrum that includes numerous forms, both known (e.g., MODY/monogenic, Ketosis-Prone Diabetes) and unknown. During the current U54 funding cycle we established the Rare and Atypical Diabetes Network (RADIANT), with a well-functioning infrastructure to identify and enroll participants with atypical diabetes; a pipeline for harmonized screening and adjudication of enrolled participants; full genomic characterization of participants via whole genome sequencing; transcriptomic characterization via RNA sequencing; quantitative plasma metabolomics; patient-specific, inducible pluripotent stem cell-based molecular physiology; enrollment of informative family members; and both standard and specialized phenotyping for each participant. In the next cycle of RADIANT, we propose to continue to recruit persons with atypical forms of diabetes to fulfill the original goals, together with discovery and analysis of the mechanisms and pathways that define these new forms of diabetes, by achieving the following Aims: 1) Continue the identification, genome sequencing, transcriptomic and metabolomic interrogation, and deep phenotyping of individuals and families with atypical forms of diabetes; 2) Discover and describe new forms of monogenic diabetes; 3) Expand and enrich the growing database to characterize atypical diabetes and recognize different genotypic and phenotypic clusters; and 4) Determine the pathophysiological mechanisms of atypical diabetes genomic variants. Thus, in the next cycle of RADIANT, our collaborative, multidisciplinary, and accomplished diabetes investigators will expand our repository of atypical diabetes cases, identify new disease mechanisms, target pathogenic pathways, advance our understanding of diabetes pathophysiology and develop an improved, etiologically based classification of diabetes.

NIH Research Projects · FY 2026 · 2018-08

Stroke is a leading cause of death and disability in the United States. In the past decade, there have been tremendous strides in discovery of beneficial approaches to treat and prevent stroke, aided in part by conduct of large-scale clinical trials in StrokeNet. The established Stroke Trials Network has conducted and executed numerous clinical trials with sufficient sample sizes, robust enrollment, timely completion, and rigorous and uniform infrastructure across sites. This application is in response to the recent NINDS request for Regional Coordinating Stroke Centers (RCC) in the NINDS Stroke Trials Network (RFA-NS-23-010). The Chicago Stroke Trials Consortium (CSTC) led by the RCC at University of Chicago (UChicago) has been an integral part of the NIH StrokeNet. In this renewal application, we expand our network to include 12 primary hospitals in the Chicago and Milwaukee metropolitan areas: UChicago Medical Center, Northwestern Memorial Hospital, Rush University Medical Center, University of Illinois at Chicago Hospital, Loyola University Medical Center, John H. Stroger, Jr. Hospital of Cook County, Medical College of Wisconsin’s Froedtert Hospital, Central Dupage Hospital, NorthShore Evanston Hospital, Hines Veterans Affairs Hospital, Lurie Children’s Hospital, and the Shirley Ryan Ability Lab. We have enlisted institutional support including agreements to utilize a federated institutional review board process (central IRB) and master trial agreements to ensure rapid implementation of future trials from each of our participating sites. The RCC aims to combine resources, faculty with diverse stroke expertise, and access to a multi-ethnic population of stroke patients spanning from children to elderly and from acute treatment to rehabilitation. The CSTC will participate in acute stroke, rehabilitation, and prevention trials, and has expertise from investigators in vascular neurology, neurosurgery, neurocritical care, neuroradiology, interventional neuroradiology, neurorehabilitation, pediatric neurology, and emergency medicine. The amassed investigators have backgrounds in all aspects of stroke research and leadership roles in many recently completed and ongoing NIH and industry-sponsored trials. The consortium has a combined geographic referral base encompassing more than 12 million people and has a history of collaboration in clinical and scientific endeavors. Drawing from the vast geographic reach of our hospitals, their resources and investigators, and substantial contributions to StrokeNet during the prior 2 award periods, the CSTC is uniquely qualified to continue to deliver a high-risk stroke patient population, provide consolidated multidisciplinary and multi-institutional expertise and leadership for StrokeNet trials, and ensure mentoring for trainees and junior faculty seeking academic careers in stroke.

NIH Research Projects · FY 2025 · 2018-08

Population Genomics of Host-Microbiome Interactions There is wide variation in the composition of the microbial communities that colonize the human body across individuals and populations, and this variation has been associated with numerous host traits and diseases. Understanding the factors that influence this variation, and the mechanism by which this variation affects host traits, is of central goal in human disease research. Although some of the variation in the microbiome is controlled by host genetics, we know very little about the genomic factors that control the interaction between humans and the microbiome and their effect on complex human disease. Disentangling genetic from environmental effects on the microbiome is challenging, and the microbiome is usually profiled in a single time point, which doesn’t account for microbiome longitudinal variation. Moreover, most of our knowledge on host-microbiome interactions consists of correlational associations, and we do not know how inter-individual and inter-population variation in microbiome composition affects host gene regulation. My laboratory’s research aims to address these critical gaps in knowledge. Research in my lab is based on the hypothesis that the microbiome can be considered a quantitative trait, and thus we can directly map host genomic factors controlling the variation in the microbiome, as well as identify individual host genes and pathways that are regulated by the microbiome. My lab’s research program for the next five years is designed to answer fundamental questions about the genomic basis of host-microbiome interactions via three broad, complementary Project Areas, aiming to: (1) develop computational techniques to integrate microbiome and host genomic data, and apply these methods to achieve a systems-level understanding of host-microbiome interactions across populations and disease states; (2) characterize the heritability of functional components of the microbiome (microbial genes, strains, and pathways) and assess the effect of life-long longitudinal microbiome dynamics on host physiology in a primate model system; and (3) use novel in-vitro and ex-vivo systems to understand the causal effect of inter-individual and inter-population variation in the microbiome on host gene regulation and describe the underlying regulatory mechanism. The proposed research program will provide a systems-level view of the molecular interactions between host genes and microbial factors in the gut across populations, environments, and diseases; a characterization of how microbiome longitudinal dynamics, as well as genes, pathways, and strains are controlled by host genetic; and a description of the mechanism with which microbes regulate host genes. These results would transform our understanding of the interplay between human genomics and the microbiome, explain how this interaction affects disease, and enable development of microbiome-based therapeutics and diagnostics that improve human health.

NIH Research Projects · FY 2025 · 2018-08

This proposal focuses on dissecting of the molecular mechanisms involved in the control of cell division, cell polarization, and morphogenesis. These simultaneously interrelated and functionally distinct processes are controlled by small GTPases, switch like proteins that primarily act at cell membranes to remodel cellular physiology. These proteins perform numerous functions in cells and tissues and their activity is highly regulated. We propose to study the role of several small GTPases during these processes in intact model organisms, including the nematode C. elegans and the fruit fly, Drosophila using a combination of live cell imaging, classical genetics, and optogenetics. We will also dissect the mechanisms responsible for the spatial and temporal activation of these GTPases which is critical for cell division, cell polarization, and morphogenesis. Given the high degree of conservation of these processes, information gained in this project could aid our understanding of certain cancers and the origin of some birth defects.

NIH Research Projects · FY 2025 · 2018-06

Abstract: We are engaged in the systematic efforts to exploit new, efficient, and broadly useful palladium/norbornene (Pd/NBE) catalysis for site-specific arene/heteroarene vicinal di- functionalization and one-step carbonyl 1,2-transposition. Our objectives in the proposed funding period include first to realize a previously unprecedented ortho oxygenation of aryl halides enabled by a new class of electrophile; second to develop direct vicinal difunctionalization of five- membered heteroarenes via both oxidative and redox-neutral approaches; and third to enable a one-step carbonyl 1,2-transposition reaction. The proposed research is expected to identify new synthetic methods and efficient catalyst systems, which should provide general and distinct approaches to access poly-substituted arenes and heterocycles commonly found in pharmaceuticals or to efficiently relocate carbonyl groups in complex molecules for generating novel “functional group-shifted” analogues.

NIH Research Projects · FY 2025 · 2018-04

PROJECT ABSTRACT African Americans have the highest breast cancer mortality rate, highest incidence rate of early-onset breast cancer, and highest incidence rate of triple-negative breast cancer in the U.S. More than 220 susceptibility loci for breast cancer have been identified by genome-wide association studies (GWAS), mainly in population of European ancestry. Polygenic risk scores (PRS), which aggregate common genetic variants identified by GWAS, have been developed to predict genetic risk of breast cancer for European ancestry women and used in clinical practice, but the PRS for African American women has suboptimal accuracy. Therefore, we propose a comprehensive analytical study that leverages several types of existing genetic datasets for breast cancer available to us and in public domains to address three specific aims. First, we aim to conduct cross-ancestry fine-mapping analysis to identify a credible set of causal variants in 237 breast cancer susceptibility loci. Then we will develop parsimonious and robust PRS from the credible set of variants. We have compiled and harmonized genetic data from breast cancer GWASs in women of African ancestry, including 18,034 cases and 22,104 controls, and leverage the association results from European ancestry (>133,000 cases and >291,000 controls) and Asian (>22,000 cases and >22,000 controls) populations. Second, we aim to develop precise PRS using genome-wide data with several novel cross-ancestry statistical methods. We will develop PRS models for overall breast cancer and its subtypes (estrogen receptor positive and negative, and triple-negative breast cancer). Then we will validate the models generated in aims 1-2 in independent datasets (>14,000 cases and >82,000 controls) from case-control studies, ongoing cohort studies, and an ongoing risk-adaptive breast cancer screening trial. Third, we will integrate the best performed PRS with existing risk prediction models that are based on non-genetic risk factors. The resulting absolute risk models have a good potential to translate knowledge from GWAS to inform the practice of genetic counseling, breast cancer screening and prevention for African Americans. It has good potential to advance racial equity in breast cancer.

NIH Research Projects · FY 2026 · 2018-04

SUMMARY Exploiting immunity to eliminate cancer cells offers tremendous new therapeutic opportunities, including the widely employed immune checkpoint blockade (ICB) agents. These approaches are challenged, however, by the multitude of mechanisms through which tumors can suppress anti-tumor immunity and render them effective in only a portion of patients. We have shown that effector T cells require high rates of glucose uptake for anabolic metabolism, and it is now apparent that cancer cells and the tumor microenvironment (TME) disrupt anti-tumor immunity in part through metabolic immune suppression. To address this barrier to immunotherapy, we examined tumor infiltrating lymphocytes (TIL) from surgically excised samples of human clear cell Renal Cell Carcinoma (ccRCC), a cancer with moderate rates of ICB response that is characterized by loss of the Von Hippel-Lindau (VHL) tumor suppressor. These tumors allowed us to show that both glucose and glutamine are available in the TME and while glucose metabolism promotes effector T cells, metabolism of glutamine restrains T cell effector function. It is unclear which glutamine-dependent enzymes or metabolites suppress T cells, but we found that Glutaminase-deficiency altered histone methylation and reduced expression of Pik3ip3, a PI3K- inhibitory protein that suppresses PI3K/mTORC1 signaling and production of inflammatory effector cytokines. To further explore mechanisms of T cell suppression by glutamine, we performed an in vivo CRISPR screen in primary TIL and found loss of Glutamine Synthetase among all glutamine-metabolizing enzymes to most effectively increase TIL accumulation. We also directly defined cell type-specific glucose and glutamine usage in the TME using radiolabeled Positron Emission Tomography tracers. In contrast to classic Warburg metabolism, tumor associated macrophages (TAM) were the dominant consumers of glucose, followed by TIL, and cancer cells, which instead preferentially consumed glutamine. Interestingly, loss of Vhl did not increase glucose uptake of RCC cells in vivo but instead increased glucose uptake in TIL and TAM. To explore these pathways in patients undergoing ICB therapy, we next performed high dimensional CyTOF analyses of peripheral blood from a longitudinal cohort of patients before and 3 weeks after start of therapy. This approach specifically identified rare but highly proliferative ICB-responsive CD8 and CD4 T cells with elevated mitochondrial potential. Based on these findings, we hypothesize that RCC genetics drive a metabolically immunosuppressive TME with abundant glutamine that suppresses PI3K signaling to impair T cell effector differentiation and function. We will study primary human ccRCC tumors and mouse RCC models to: (1) Test how nutrients in the ccRCC TME and tumor genetics influence TIL function and metabolism; and (2) Determine how glucose and glutamine metabolism in the TME promote or suppress anti-tumor immunity. Together, these studies will establish mechanisms by which glutamine impairs T cell differentiation and test new potential targets to overcome metabolic immune suppression in the TME to improve anti-tumor immunity.

NIH Research Projects · FY 2025 · 2017-12

Summary: Deep vein thrombosis (DVT) is a major public health problem that affects 640,000 Americans each year, and accrues $10B in healthcare costs. For critical thromboses, the American Heart Association and Society for Interventional Radiology recommend thrombolytic drugs be administered to break down the thrombus and restore flow in the vessel. Thrombolytic drugs are not effective for the 43% of DVT cases with chronic thrombus, resulting in poor clinical outcomes for these patients. Adjuvant strategies are therefore needed to ensure effective treatments for the entire thrombus. The scientific premise of this renewal project is combining thrombolytic drugs with histotripsy, an ultrasound therapy that ablates tissue with the mechanical action of bubble clouds, will improve outcomes for DVT patients. In the prior period of this project, we established this combination treatment (histotripsy+) addresses all thrombus components, and resulted in better outcomes than either approach individually in vitro and in vivo. In contrast, only a subset of thrombus components could be treated with histotripsy or thrombolytic alone, which increases the likelihood for vascular re-occlusion. These lessons have informed our revised approach in this Renewal Project, with an objective to address current gaps that limit clinical deployment of histotripsy+. In Aim 1, we will upgrade our histotripsy+ instrumentation. A phased source will be produced that generates bubble activity along a 1 cm length of thrombus for single transmitted pulses, and enables treatment for up to a 5 cm segment with electronic steering. Bubble activity will be monitored volumetrically with a coaxial matrix imaging probe using our passive and active imaging algorithms. We will adjust transmitted pulses in real time to account for defocusing from tissue heterogeneity using the send/receive capabilities of the phased, cylindrical transducer. Finally, treatment protocols and imaging markers will be established that ensure effective outcomes based on time-resolved measurements of in vitro clot degradation, and confirmed with ex vivo chronic human specimen. Studies in Aim 2 will assess the safety of histotripsy+ for DVT. Mechanisms of platelet activation during histotripsy+ will be assess in vitro, and effective antithrombotic strategies to counter will be determined in vivo. For chronically thrombosed veins that have a reduced compliance to strain, we will identify exposure conditions that effectively treat chronic DVT but avoid vascular rupture in vivo. Additionally, we will assess treatment-related changes to cellular composition of treated veins with our microfluidics-based scRNA-Seq technique. Finally, studies in Aim 3 will gauge the influence of thrombus age (0 to 30 days) on treatment outcomes of histotripsy+ to develop personalized treatment strategies based on stage of disease. Following successful completion of the proposed studies, we will have produced a validated system for rapid treatment of DVT, with sufficient data to confirm the safety and efficacy needed for clinical testing. Further, new information will be gathered to address currently intractable venous thrombi.

NIH Research Projects · FY 2026 · 2017-09

PROJECT SUMMARY – Overall This is the revised submission of the first competing renewal proposal for the “ChicAgo Center for Health and EnvironmenT (CACHET)” – the first NIH P30 Environmental Health Sciences (EHS) Core Center in the Chicago area established in 2017 with an equal partnership between the University of Chicago (UofC) and the University of Illinois at Chicago (UIC). With synergistic partnership between the two universities with complementary strengths, CACHET promotes multidisciplinary EHS research among clinician, laboratory, and population scientists to evaluate, delineate, and ultimately reduce environmental health related risks among residents of Chicago and beyond. The continuation of a dedicated EHS research center in Chicago is warranted by deep- rooted environmental conditions and their associated health outcomes across population sub- groups. In this context, the CACHET mission is to understand how environmental exposures in urban settings affect human biology and health. Our goal is to generate actionable scientific knowledge that supports efforts to reduce chronic disease burden and improve population health. While there was some EHS research at both institutions prior to the establishment of CACHET; over the past 3.5 years, CACHET has integrated this research, brought researchers together, formalized and steered intra- and inter-institutional collaborations, and significantly enhanced EHS research support infrastructure in the Chicago area. Specifically, CACHET has established Biomarkers and Microbiome Cores, a dynamic Pilot Project Program (PPP), a vibrant Community Engagement Core (CEC), and a highly translational Integrated Health Sciences Facility Core (IHSFC) – all new to the Chicago area. Within this short time frame, and despite the recent pandemic, CACHET has made positive impacts on interdisciplinary and inter-institutional collaborations, multi-sectorial partnerships among community/city/state agencies, and translational EHS discoveries. Leveraging our progress and lessons learned so far, and responding to reviewers’ critique of our first resubmission, we are moving forward by i) streamlining CACHET focus group structure to improve interactions, synergy, and translation, ii) better leveraging the UofC- UIC complementarity and institutional infrastructure to maximize CACHET efficiency, iii) responding to the P30 RFA new emphasis on translational EHS research, and, iii) addressing NIEHS strategic mission. We have revamped the CEC with new leadership and a community-focused agenda; we formed a “Environmental Biomarkers Core (EBC)” by merging the previous ‘Biomarkers’ and Microbiome’ Cores with enhanced access to other institutional Omics Cores (not funded by CACHET); we refined the IHSFC to augment its services to access and leverage large cohorts established and led by CACHET members; and we have taken initiatives to broaden EH research capacity in Chicago through pilot projects and tailored career development.

NIH Research Projects · FY 2025 · 2017-09

In 2017, the University of Chicago Medicine Comprehensive Cancer Center (UCCCC) was among the first recipients of the National Cancer Institute (NCI) Youth Enjoy Science (YES) Research Education Program (R25) grant, launching Chicago EYES (Educators and Youth Enjoy Science) on Cancer. EYES serves high school students, college students, and science educators from across Chicago, engaging them in cutting-edge cancer research, science outreach, and biomedical career exploration. To date, the program has enrolled 70 student trainees and 14 teacher research fellows. Evaluation data reflect growth in trainees’ research skills and expertise; knowledge and self-confidence regarding research professions; and commitment to pursuing a research career. Ninety-six percent of student alumni remain committed to careers in STEM, and more than a third are pursuing a cancer specialization. Teacher research fellows described their experience as transformational, imparting new insights about science learning and practice that not only strengthened their skills as educators, but also improved their ability to relate to their students. Renewed funding is essential to build on the success of EYES. Specifically, we aim to: 1) Equip young people with specialized skills and expertise to build their competencies as entry-level cancer researchers; 2) Broaden young people’s awareness of cancer-related career opportunities and empower them to make informed, strategic plans to accomplish career goals; 3) Strengthen support for young people’s career development by engaging members of the scientific and local communities, and young people’s immediate families, in their education and training; and 4) Maintain a robust network of support for program alumni. Over the next five years, we expect to enroll at least 70 new high school and college students, and at least 8 teacher research fellows, in the full two-year program. Through our partnerships with Chicago Public Schools, the Museum of Science and Industry, Chicago Access Network Television, and other local institutions, we anticipate engaging more than 1000 community members each year in STEM enrichment and outreach activities. In these ways, Chicago EYES on Cancer will continue to empower the city’s diverse and talented youth to pursue careers in biomedicine, supporting NCI’s mission to build a skilled cancer workforce, advance scientific knowledge, and help all people live longer, healthier lives.

NIH Research Projects · FY 2025 · 2017-09

The proposed renewal application for African Cancer Leaders Institute (ACLI) is a “meeting within a meeting” designed to coincide with conferences organized by the African Organization for Research Training In Cancer (AORTIC) conference, beginning with the forthcoming, “Cancer in Africa: Implementation, Workforce, and Opportunities” in Dakar, Senegal, November 3-8, 2023. The ACLI will identify early career researchers in global cancer research who are capable of leading interdisciplinary teams to improve cancer treatment in Africa. The long-term goal of ACLI is to provide an intellectually stimulating platform to propel emerging global cancer leaders from Africa and the US to receive support for innovative collaborative research in Africa, and to stimulate an African network for emerging leaders in global cancer research. The ACLI platform will have annual goals and objectives set by the Education and Research Sub-Committees of AORTIC in collaboration with the ACLI program Organizers. The ACLI will widely solicit competitive applications from aspiring leaders in Africa and the US. During the past funding cycle, three cohorts of ACLI participants (60 total) were recruited and participated in AORTIC Conferences in Durban in 2017, Maputo in 2019 and Senegal in 2022 during a mini-retreat for ACLI members and AORTIC Council Members at the 1st African Regional Cancer Conference (ARCC) planned and hosted by AORTIC Leadership in West Africa. Awardees from all cohorts were invited to participate and 21 attended in person. It was gratifying to note enthusiastic participation by investigators from West Africa, especially those from French and Portuguese speaking countries. Most of the ARCC lectures were given by ACLI participants and researchers working in Africa who reported having received 6 NIH and 5 foundation grants. ACLI participants were unanimous in endorsing the need for a regional conference every other year that will provide greater capacity building opportunities and more succinct leadership programing for ACLI. For this renewal application, 10 Emerging Leaders will be fully-funded for travel to attend the AORTIC conference and participate in ACLI activities. Five emerging Leaders from high-income countries with meritorious abstracts and application will be selected for Merit travel award in order to continue to forge professional relationships and foster peer mentorship. ACLI participants will mostly network in groups of 6-8 with conversations on specific topics facilitated by Faculty, and they will also attend scientific sessions. For peer mentoring, sessions will be arranged for ACLI participants to discuss and evaluate concepts presented at the conference to enhance learning and career development experience. Each new ACLI participant will be asked to prepare a brief 15-minute overview of career accomplishments and plans for their career development activities. We will continue to track several metrics including conference evaluations, career landmarks, publication records and the number of ACLI members who compete successfully for Africa focused NIH/NCI grants e.g K43, K07, K23, R21 etc. Lastly, in keeping with priorities of the NIH/NCI, ACLI participants will be encouraged to participate in advocacy training to provide guidance for Africa Center for Disease Control and African Governments with a strong commitment to strengthen cancer research capacities of in their own countries. Through reverse innovation, ACLI fostered partnerships has the potential to benefit All Americans.

NIH Research Projects · FY 2025 · 2017-09

PROJECT SUMMARY/ABSTRACT Language and communication impairments (aphasia) are the defining features of the clinical neurodegenerative dementia syndrome primary progressive aphasia (PPA), which can be caused by Alzheimer’s disease (AD) or frontotemporal lobar degeneration. The devastation of communication negatively impacts quality of life for persons living with PPA and their care partners. Communication difficulties in PPA can also reduce life-space mobility including shrinking social interactions and lowering participation in community activities. Nonpharmacological interventions, including speech-language and psychosocial intervention, may offer significant benefit to the quality of life for persons with PPA and their care partners, but have historically lacked efficacy evidence as well as guidelines to direct best clinical care practices. We have been changing this landscape, through the development of the Communication Bridge (CB) intervention with strategically staged, rigorous clinical trials that are on a path towards implementation. The CB1 trial established feasibility of delivering our intervention at a global scale via telepractice and demonstrated gains in functional communication outcomes that were maintained 6-months post baseline. Next, the CB2 trial provided the first rigorous Phase 2a, Stage II, superiority, randomized controlled trial (RCT) of speech-language intervention in PPA. CB2 interim analysis conditional power results suggest a high probability of trial success (>80%) but also identified a need for greater psychosocial education and counseling. Thus, the current application proposes the CB3 trial designed to optimize the intervention by testing whether the addition of psychosocial education and counselling (PEC) to speech-language intervention (Experimental arm) is superior to an active Control intervention. The RCT will be complemented by Aim 1a, which will maximize pragmatic trial readiness following the Readiness Assessment for Pragmatic Trials (RAPT) tool; and Aim 2, which will assess functional outcomes with novel wearable sensors to objectively measure life participation using a ‘Life-Space Mobility’ framework. Trial outcomes will inform future pragmatic trial design. The translational potential is high since the delivery model and primary outcomes are aligned with current clinical practice. In the absence of a definitive cure for AD and related neurodegenerative diseases, it is important to identify and evaluate strategies that help individuals maximize their quality of life, and this project will help fulfill this need.

NIH Research Projects · FY 2024 · 2017-09

PROJECT SUMMARY Arsenic contamination of food and drinking water is a serious global health issue in the U.S. and worldwide. Arsenical skin lesions are a common and early sign of arsenic toxicity, but exposure to arsenic is also associated with risk for various types of cancer, cardiovascular disease, non-malignant respiratory disease, and shortened life span. A major focus of epidemiological research on arsenic exposure has been understanding genetic susceptibility to arsenic toxicity. Genetic studies have discovered roles for both inherited variation (e.g., AS3MT variants) as well as dynamic features of the genome (i.e., telomere length) in susceptibility to arsenic toxicity and response to exposure. Additional research is needed to fully understand these gene-environment relationships. The last decade of research on genetic susceptibility to disease in humans has clearly demonstrated that large studies with genome-wide measurement are highly likely to deliver discoveries that are re-producible. Thus, we propose creating a large genomic data resource in the context of an epidemiological study of arsenic exposure in rural Bangladesh. We will use this resource to identify the features of the human genome that reflect susceptibility or response to arsenic exposure. Our first goal is to extend our ongoing work on the genetics of arsenic metabolism efficiency (AME) and GxE (gene-by- environment interaction) to identify inherited variants that influence arsenic metabolism or arsenic toxicity. Under this goal, we will investigate the biological mechanisms of arsenic-related variants and evaluate the utility genetic information for exposure reduction. Achieving this goal will entail activities such as genome-wide association and heritability studies of AME and arsenical skin lesion risk, genome-wide searches for GxE, estimating the effects of SNPs on arsenic-related health outcomes, and evaluating the impact of returning genetic results to participants on exposure-related behaviors. Our second goal is to extend or our work on arsenic and telomere length to identify additional dynamic features of the genome that reflect biological response to arsenic or susceptibility to arsenic toxicity. Achieving this goal will entail testing numerous genomic features for association with arsenic exposure and arsenical skin lesion status, including somatic chromosomal losses and point mutations, DNA methylation, epigenetic aging, and mitochondrial DNA mutation and copy number. If successful, this project will provide novel biomarkers of susceptibility and toxicity as well as biomarkers of the biological effects of arsenic exposure. The biomarkers identified will provide information useful for (1) identifying subgroups of highly susceptible individuals, (2) understanding biological mechanisms underlying susceptibility and toxicity, and (3) motivating susceptible individuals to reduce their exposure. Furthermore, we will continue developing technologies for targeted measurement of copy number variable regions for large scale epidemiological and environmental health research. This work has the potential to have transformative impact not only on knowledge, but also on both global and local environmental health.

NIH Research Projects · FY 2025 · 2017-09

For ITM 3.0, we request continued funding for the TL1 Postdoctoral Program, which over the past five years has provided training in clinical research and biomedical informatics to 18 postdoctoral fellows. This current postdoctoral TL1 program was begun in 2017, replacing an earlier predoctoral program; it is comprised of collaborating programs at UChicago and Rush, and its goal has been to prepare postdoctoral trainees for careers as independent and collaborative translational researchers through the integration of clinical research and biomedical informatics training. For ITM 3.0, we will build on the existing program structure and new training opportunities in clinical research, biomedical informatics, and public health to offer interdisciplinary postdoctoral research training that provides fellows with a guiding framework and skillset to help advance health through translational research. The new iteration of this program, called the TL1 Postdoctoral Training Program in Clinical Research, Biomedical Informatics, and Health, will incorporate research training opportunities at UChicago, Rush, and Loyola University Chicago to offer didactic training in clinical research, informatics, and public health. In addition, the program will provide faculty-mentored research opportunities and peer learning opportunities. Postdoctoral training programs such as the TL1 are critical to building a strong, enduring pipeline for developing the next generation of leaders in clinical and translational research who prioritize advancing health as a goal of their research. Trainees will engage in this postdoctoral program after completing predoctoral training in graduate or medical school, and before a faculty appointment. The purpose of this postdoctoral training is to provide protected time and tuition support for early-career investigators to pursue advanced coursework and engage in mentored research, so they can successfully compete for faculty jobs, career development awards, and independent research funding.

NIH Research Projects · FY 2025 · 2017-09

The goal of the ITM CTSA KL2 Scholar program is to produce accomplished researchers capable of utilizing the tools of clinical and translational research to improve the understanding or treatment of human disease. Research topics can relate to any aspect of clinical and/or translational research and to any patient population or disease group. Any suitable research approach can be employed. However, relevance to the understanding or treatment of human disease must be demonstrated. In ITM 3.0, we will particularly emphasize the impact of health challenges during the training of our KL2 Scholars across the translational research spectrum, so that they are able to consider issues related to all persons and social, environmental, behavioral, and psychological (SEBP) factors, and account for these in complex designs and approaches. Our program’s track record demonstrates a high degree of success in supporting junior faculty to successful academic research careers. Since inception of our KL2 program in 2008, we have had or currently have 30 Scholars in our program. Of these 30 Scholars, 13 (43%) have transitioned to R01 or comparable funding with several still likely to make this transition in the near term. This demonstrates the ability of our program to produce Scholars with high-impact, innovative research that aligns well with the emerging directions at NIH and in the scientific community. We anticipate supporting ~2 years of multidisciplinary training for each selected junior faculty member, who will devote ≥75% effort to investigation and training (≥50% for surgeons). The program will include five KL2 Scholars at any time (drawn primarily from UChicago and Rush, but occasionally from other ITM affiliates), and its impact will be extended greatly beyond this relatively small number through co-training and extensive interactions with K Scholars in other career development programs at the lead ITM institutions (UChicago and Rush University) and its affiliates as well as with participation of numerous individual K-award (or equivalent) recipients and K-award aspirants at all ITM institutions.

NIH Research Projects · FY 2025 · 2017-09

The University of Chicago – Rush University Institute for Translational Medicine (ITM) was created in 2007 to assemble, integrate, and create the intellectual, administrative, and physical resources required to catalyze research and research training in Clinical and Translational Science. We have trained university scientists and health care providers as well as stakeholders from concerned communities to work together to determine the biological, behavioral, and social determinants of disease; to develop and test interventions directed toward those mechanisms; and to achieve these goals in a way that is rigorous, efficient, ethical, respectful of, and responsive to our communities’ priorities and values. The ITM has capitalized on outstanding intellectual and physical resources throughout UChicago, Rush, and ITM affiliate institutions – Loyola University Chicago, NorthShore University HealthSystem, Advocate Aurora Health Care, and Illinois Institute of Technology – and on substantial multi-institutional investments to build the sustainable infrastructure for a transformative, energetic, and self-improving home for clinical and translational research. Now, we pursue a bold guiding vision for “ITM 3.0” – that improving health requires accounting for and addressing social, environmental, behavioral, and psychological (SEBP) factors that can affect health. Focus on SEBP is critical because: 1) SEBP factors interact with human biology to exacerbate or cause disease and injury, and 2) illness of any origin can compound the negative effects of adverse SEBP factors. Since both SEBP and biological systems, and their interactions, determine health, our CTSA hub must provide investigators, trainees, and stakeholders with the resources and knowledge to account for and address health disruptors throughout both systems. Our strategy to implement this vision is to create new training mechanisms, research platforms, communications channels, and safeguards against harm to ensure that all ITM investigators and institutions approach health problems with a wider-angle SEBP lens in an ethical way. Then, our scientific, institutional, and community stakeholders can together design, test, and disseminate biological and/or SEBP-directed interventions at the levels of individual, community, and society to improve mutually defined health concerns. ITM 3.0 will work hand-in-hand with partners throughout Chicagoland and the nation, combining academic rigor with community wisdom to conceptualize, develop and deploy innovative and ethical interventions/practices to achieve our common goal.

NIH Research Projects · FY 2024 · 2017-09

PROJECT SUMMARY / ABSTRACT Aggregates of amyloid peptides, such as amyloid fibrils are highly cytotoxic, as exemplified by the role of amyloid β (Aβ) in Alzheimer's disease. To maintain a healthy proteome, a number of proteases target the monomeric form of amyloid peptides because this form fuels both seeding and elongation of amyloid fibrils. Insulin degrading enzyme (IDE) is a 110 kDa metalloprotease that degrades various amyloid peptides, including Aβ and three blood glucose-regulating hormones, namely insulin, amylin, and glucagon. Defects in IDE alter the progression of type 2 diabetes mellitus and Alzheimer’s disease in animal models and are linked to these diseases in humans. IDE inhibitors can control blood glucose level in mice and hold promise for treating diabetes. One of the key steps in the IDE catalytic cycle is the selective recognition and unfolding of amyloid peptides prior to degradation. Our premise is that the understudied conformational dynamics of IDE provide the mechanical basis for the unfolding of peptide substrates. Thus, we can leverage our understanding of these processes to selectively modulate the activity of IDE towards specific substrates. Our long-term goals are to elucidate the molecular details of how IDE selectively recognizes amyloid peptides and utilize this knowledge to develop novel IDE- based therapies to improve the human condition. Toward this goal, we have integrated ensemble structural determination and solution-based methods to show that IDE is a member of the chamber-containing protease, aka cryptidase, family that uses a sizable catalytic chamber to engulf monomeric amyloid peptides. We have also generated a working model that explains how IDE uses two key conformational switches to selectively degrade amyloid peptides. Our objectives for this application are to determine key unsolved conformational states and probe the conformational dynamics of IDE during the catalytic cycle by applying state-of-art integrative structural approaches. We will then combine MD simulation and screening to identify strategies to modulate the catalytic activity and selectivity of IDE. Our research rationale is that a deeper understanding of the regulation and functions of IDE will allow us to modulate its activity through engineering or novel small molecules and ultimately facilitate the design of IDE-based therapies to combat proteostatic imbalances. We will use time- resolved cryoEM and SAXS to understand the structural basis for substrate recognition during the key time window when IDE first encounters substrate in combination with advanced cryoEM image processing algorithms and MD simulation to address how IDE motions can unfold physiologically relevant substrates. We will apply the knowledge gained from the substrate recognition and unfolding studies to develop a screening strategy to identify methods to selectively modulate the degradation of Aβ by IDE. This work will significantly enhance our understanding of the IDE catalytic cycle by defining key conformational states under physiologically relevant conditions and offer a platform to merge integrative structural analysis and MD simulation towards the discovery of innovative enzyme modulating strategies as the developmental foundation of novel IDE-based therapies.

NIH Research Projects · FY 2026 · 2017-08

Many of major autoimmune diseases are sexually dimorphic. Systemic Lupus Erythematosus (SLE), scleroderma, multiple sclerosis, Sjogren’s syndrome, and some forms of Type 1 diabetes (T1D) are primarily occurring in females. It has been attributed to multiple factors including expression of the genes encoded by sex chromosomes, hormonal regulation of gene expression, and lately to unexpected regulation by commensal microbiota. Thus, understanding of sexual dimorphism of diseases requires that the problem be approached by a combination of different strategies. In this proposal, we take advantage of our abilities to perform state of the art experiments using genetically modified and gnotobiotic animals with original and constantly developing computational methods. Our preliminary data demonstrates the efficiency of such an integrative approach to the problem. We have suggested a ‘dual signal’ model of autoimmunity involving regulation by microbes and sex hormones. Accordingly, hormonal and microbial influences do not have to be simultaneous: they may be important at different stages of development or disease progression. We are focusing on T cell-intrinsic and T- cell-extrinsic effects of Androgen Receptor (AR) and the mechanisms of microbiota’s effect on T1D development. Given the complexity of the problem, we plan to pursue several carefully selected goals that will continue to lay foundation for the future expansion of research in this important area. Specific Aim 1. Determine the input of T cell-intrinsic and T cell-extrinsic mechanisms in the sexual dimorphism of T1D. 1.1. Determine whether all cells involved in AR-mediated protection from T1D are of bone marrow origin; 1.2. Define the role of myeloid cells in male protection from T1D; 1.3. Test the contribution of myeloid cells in T cell transfer experiments; 1.4. Test a role that transcription factor AIRE plays in sexual dimorphism of T1D. Specific Aim 2. Investigate the influence of AR signaling on T cell selection and function 2.1. Determine the influence of AR on the TCR repertoires; 2.2. Determine how the properties of the TCR affect the influence of AR on repertoire selection; 2.3. Study the role of AR in regulation of interferon gamma (IFNg) related to autoimmunity; 2.4. Study the role of AR in regulation of the IFNg locus; Specific Aim 3. Determine where and when the microbiota amplifies AR effects on T1D development. 3.1. Test T1D development in GF animals with conditional AR deficiencies; 3.2. Determine whether microbes contribute to changes in immune cells properties during their development; 3.3. Establish the timeline to imprinting males to become resistant to T1D by the microbiota; 3.4. Determine which immune-related pathways are affected by the microbiota.

NIH Research Projects · FY 2025 · 2017-08

PROJECT SUMMARY Single cell technologies, in particular single cell transcriptomics, have been applied to numerous areas in biological and biomedical research and become a powerful tool for complex tissue characterization. Despite its ever-growing throughput and complexity, the development of analytical tools for single cell genomics has fallen behind the technological advances. The overarching goal of this proposal is to address some of the most pressing analytic challenges facing profiling and interpreting single cell genomics data, including: 1) lack of differential expression analysis methods that properly account for within-sample cellular heterogeneity; 2) lack of cis-regulatory inference methods that leverage multi-omics data; and 3) lack of proper methods to perform eQTL mapping in population-scale scRNA-seq studies. In the proposal, we will work on the following aims: Aim 1. Develop a differential expression analysis framework that better resolves sample heterogeneity and combats false discoveries for single cell data. Aim 2. Develop Bayesian model selection methods that infer cis- regulatory relationships from multi-omics data. Aim 3. Develop eQTL mapping methods that accommodate multiple cell types and experimental conditions in population-scale scRNA-seq studies. All methods will be implemented in user-friendly software and disseminated to the scientific community. Successful achievement of Aims 1 and 2 will dramatically increase the power of routine single cell genomics analysis, facilitating the application of these cutting-edge technologies to translational and clinical studies. Successful achievement of Aim 3 will provide new ways to comprehensively characterize the genetic architecture underlying gene expression that is specific to both cell-type and experimental-condition, ultimately facilitating the understanding of common diseases and disease-related complex traits.

NIH Research Projects · FY 2025 · 2017-07

The Integrative Training in the Neurobiology of Addictive Behaviors Program at The University of Chicago offers training for both pre- and postdoctoral trainees in drug abuse-related research. Our core faculty trainers are productive researchers with successful training credentials. Their expertise ranges from molecular biology, electrophysiology, pharmacology and animal models of drug addiction, to the social, behavioral and psychopharmacological aspects of human drug use, including etiology, treatment and drug policy. Quantitative approaches and reproducibility are emphasized. Our goal is to prepare the next generation of scientists to investigate the etiology, prevention and treatment of drug abuse with integrative approaches. We propose a program for 3 predoctoral and 4 postdoctoral trainees. Trainees will be supported by the Training Program for 1-3 years (usually 2 years). Trainees obtain specialized intensive training in their ‘home’ laboratories, but they are also exposed to the full breadth of addictions research outside their own area. To ensure that there is substantial interaction among the trainees, and between trainees and trainers, we schedule bi-weekly meetings consisting of journal club presentations and seminars by invited speakers. Didactic courses range from molecular cellular neuroscience to systems and behavioral neuroscience, from statistics to computational neuroscience and bioinformatics, from genetics and epidemiology to treatment and policy. One other mechanism by which our T32 has enhanced training experience is the “externship” program, in which our trainees receive mentored experiences in laboratories or settings removed from their own. The organizational structure includes an Executive Committee making overall training decisions, a Selection Committee to ensure a good flow and balance of trainees, a Program and Review Committee to monitor trainees’ progress, and an External Advisory Committee to provide expert outside consultation. The University of Chicago provides a unique environment with both a long history of interdisciplinary collaboration and recently a significant commitment to neuroscience research. This provides a rich intellectual context for trainees in drug abuse related research. In addition to the trainees supported by the T32, we have added Associate Members so that any trainee who is interested in addiction research can participate in any of the T32 sponsored activities. This allows us to bring together other trainees and faculty from across campus to raise consciousness about addiction research and its relevance to other disciplines. It brings in new expertise to the group and significantly enriches training opportunities.