University Of Chicago

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY/ABSTRACT The landscape of biomedical research is changing rapidly due to major technological and conceptual advances, creating new research opportunities and expansion in the scope of occupations while posing challenges for graduate training in quantitative and multidisciplinary science. Furthermore, an emphasis on best practices in graduate education and mentorship has emerged from socioeconomic shifts. To respond to these ongoing developments and the needs of students and the broader society, the Department of Biochemistry & Molecular Biology (BMB) and the Department of Chemistry (Chem) at The University of Chicago propose an interdisciplinary, predoctoral training program directed at the interface of the chemical and biological sciences (CBI) that aims to recruit, educate and train a diverse, new generation of biomedical scholars by deploying new best practices in training, mentoring, and education to promote rigorous cross- disciplinary research while developing quantitative literacy and maintaining depth in the core discipline, thereby preparing them for success in careers that require scientific training. The program benefits from outstanding faculty and students and introduction of new courses in interdisciplinary science. The 25 training faculty consists of twelve faculty with appointments in BMB (one with a joint appointment in Chemistry), ten faculty in Chemistry (one with a joint appointment in BMB), two in the Ben May Department for Cancer Research, and one in Molecular Engineering. Strategies to develop cross-disciplinary training include: (1) satisfactory completion of a core course in Chemical Biology and a breadth course in the department of the other scientific discipline; (2) cross-disciplinary thesis research; (3) participation in a series of monthly meetings throughout the academic year designated as "Integrative Discussions at the Interface of Chemistry & Biology" to gain acquaintance with theoretical concepts and methods; (4) participation in two quarterly meetings focused on advanced chemical tools in biology (ACT-Bio) and biological problems that require chemical solutions (BPRCS); (5) participation in two in two annual half-day events: a CBI Minisymposium and an “in-house” poster retreat; and (6) workshops to promote quantitative literacy and rigor and reproducibility. Participation in a division-wide career development program helps students explore and prepare for different career paths. The broad scope of the interdisciplinary research interests of the faculty strengthened through collaborative research and teaching ensures a wide variety of opportunities for meaningful cross-training. The program will promote excellence in mentorship through more frequent advising, mentoring compacts and required annual faculty mentorship training. Through active participation in pipeline, outreach, and bridge programs, and through participation in graduate admissions and faculty recruitment, program faculty will promote the recruitment and retention of an increasingly diverse scientific community. An external advisory committee and professionally implemented evaluation instruments will guide improvements to the program.

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY/ABSTRACT This 5-year K08 training program is designed to facilitate my (Dr. Lin Shen) career development in preparation of my independent research career as a physician-scientist. My long-term goal is to study the pathogenesis and, potentially, the therapy of autoimmune diseases. This proposal focuses on how inhibitory pathways restrain abnormal TCR signaling strength to achieve peripheral tolerance. Central guidance and the training environment will be provided by my primary mentor, Dr. Arthur Weiss, an expert in TCR signaling. Further expertise will be provided by a strong advisory panel of experts in lymphocyte signaling, immune tolerance, autoimmunity and transcriptomic profiling. A training plan with experimental research, didactics, and seminars has been developed to advance me towards my career goals. The extensive resources and support at the UCSF will facilitate my pathway to independence and my long-term goals. Dysregulation of TCR signaling has long been recognized to play important roles in the pathogenesis of autoimmune diseases. However, how inhibitory pathways are engaged by enhanced TCR signaling strength to regulate peripheral tolerance and prevent autoimmunity remains incompletely understood. The cytoplasmic tyrosine kinase ZAP70 plays a requisite role in TCR signaling. Two ZAP70 hypermorphic mutants, the stronger W131A and the weaker R360P, interfere with autoinhibition and have varying effects on TCR signaling. As a consequence of enhanced basal signaling, OTII-TCR transgenic W131A T cells exhibit marked upregulation of inhibitory receptors and acquisition of an anergic phenotype. The ZAP70 R360P mouse mutant that I generated derives from a familial severe autoimmune syndrome. R360P mice failed to develop overt autoimmune disease on a C57BL/6 background but exhibited expansion of regulatory and anergic T cells. Strikingly, OTI-TCR transgenic R360P T cells showed enhanced responses to weak and self-peptides. Introducing deficiency in Cbl-b, a negative regulator for TCR signaling, resulted in enhanced R360P-OTI T cell responses to a weak agonist peptide and reversed functional anergy in W131A-OTII T cells. Therefore, I hypothesize that increased TCR signaling strength renders T cells subject to greater control by inhibitory pathways but may confer upon them greater sensitivity to disruption of these inhibitory pathways. In this proposal, I will take advantage of the R360P and W131A mouse models to study how enhanced TCR signaling strength and inhibitory pathways are coupled together to either maintain or subvert peripheral tolerance. In Aim 1, using a range of biochemical techniques and transcriptomic profiling, I will dissect how TCR signaling strength is dynamically coupled to inhibitory programs. In Aim 2, I will study whether augmented TCR signaling strength promotes sensitivity to the disruption of negative regulatory pathways. This study will provide new mechanistic insights into how these opposing signaling pathways integrate to impact T cell antigen sensitivity and to regulate peripheral tolerance and the quality of immune responsiveness.

NIH Research Projects · FY 2025 · 2022-06

Project Summary This R01 proposal outlines a research plan which uses targeted nanomedicine to enhance disease- modifying molecular mechanisms both in the acute injurious phase and in the subsequent chronic fibrotic phase of viral-induced pneumonitis. The overall goal of this proposal is to use nanomedicine to modify specific cellular subtypes during the lung disease process. Acute and chronic lung diseases are major causes of mortality and morbidity in the US. Acute respiratory distress syndrome (ARDS), caused by widespread endothelial barrier disruption and uncontrolled cytokine storm, is the major cause of death in critically ill influenza and COVID-19 patients. Furthermore, pulmonary fibrosis, progressive scarring in injured lung, is a major sequelae of viral pneumonia. Early analyses showed that discharged COVID-19 patients are at high risk for developing pulmonary fibrosis. Currently, there are few pharmacological treatments that directly targets ARDS, and available therapeutic options for pulmonary fibrosis remain suboptimal, underscoring unmet medical needs in a heightened state due to COVID-19 pandemic. Strongly supported by our published and unpublished in vivo results, we believe that targeted nanomedicine approaches have tremendous potential to treat ARDS and pulmonary fibrosis, which will be comprehensively tested in vivo in this application. Aim 1 will test the therapeutic effectiveness of specifically reducing endothelial dysfunction in acute lung injury (influenza or SARS-CoV-2) in mice and perfused human lungs using a VCAM1-targeting, KLF2 mRNA-encapsulated nanoparticles. We anticipate that specific endothelial KLF2 overexpression will reduce acute lung injury. Aim 2 will test the therapeutic effectiveness of specifically targeting lung fibroblasts in chronic pulmonary fibrosis (bleomycin) in mice and human lung slices using PDGFRB-targeting nanoparticles to deliver shRNAs against TXNDC5. We anticipate that specific fibroblast inhibition of TXNDC5 will reduce lung fibrosis.

NIH Research Projects · FY 2025 · 2022-06

Project Summary/Abstract HLA-F is a nonclassical class I MHC (Ib) molecule that has been found expressed on a variety of cancers, shown to play a role in HIV and adenoviral infection, the neurological autoimmune disease ALS and is expressed throughout pregnancy. Despite the potential importance of this protein in these conditions, little is known about this molecule in terms of its function or even in which conformational state it is expressed. We have recently shown that, in addition to being expressed as a heavy chain only state, or open conformer (HLA-FOC), HLA-F can also be expressed as a bon fide peptide presenting molecule, associated with the β2m subunit (pHLA-F). Peptides are presented in an unconventional way, with the N-terminus not anchored within the groove and the potential for post-translational modifications featuring in peptide anchoring. Despite these advances, there remains much unknown about how these conformer states are regulated, how it engages its various receptors in each of these conformer states, and the role of HLA-F in its various environments of tumor surveillance, autoimmunity and reproduction. Thus, the aims of this proposal focus on addressing these questions and are: Aim 1: To investigate, structurally and functionally, the various conformer states that HLA-F adopts in human health and disease. We will pursue structural studies of the HLA-F isoforms to understand how these two states differ from each other. Using conformer-specific antibodies, we will determine what cell types express which (or both) forms and how this differs between healthy and disease cells. We will also pursue peptide elution studies from a range of human sources to determine if the peptide repertoire shifts depending on cellular origin or disease. Aim 2: To identify and analyze the factors that regulate the production or interchange of HLA- F conformers and splice forms in a cell. We will explore the cellular factors that may play a role in switching HLA-F between peptide-loaded and HLA-FOC as well as an intriguing splice variant of HLA-F of unknown function. Finally, in Aim 3 we seek to establish the receptor repertoire that engage HLA-F in its various conformer states, determine the molecular basis for their association and study the functional consequences of their binding. We will employ the structural, biophysical and functional expertise of the Adams lab to determine the receptor repertoire that engage these conformer states of HLA-F and study them at the functional and molecular level.

NIH Research Projects · FY 2025 · 2022-06

PROJECT SUMMARY Endothelial mechano-transduction mechanisms are instrumental to vascular health and disease but targeting disease-causing mechano-sensing pathways remains extremely challenging. For instance, atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed blood flow activates endothelium; however, current atherosclerosis therapies mainly target systematic risk factors but not the vasculature per se. This underscores the significance and unique opportunity to identify and target novel mechanosensitive mechanisms in activated endothelium subjected to disturbed flow. This proposal aims to first delineate novel endothelial mechano-sensing mechanisms and moreover, devise innovative precision nanomedicine approaches targeting these disease-causing mechano-sensitive pathways. This R35 mechanism will provide us a unique opportunity to synergistically combine our efforts in endothelial biology (R01 HL136765) and vascular nanomedicine (R01 HL138223), testing paradigm shift hypotheses related to endothelial mechanotransduction and addressing an unmet medical need in vascular therapies. Specifically, seminal work from us and colleagues along with our unpublished data identified three new layers of molecular controls of endothelial mechano-transduction: epi-genome (DNA chemical modification), epi-transcriptome (mRNA chemical modifications) and metabolism (glycolysis and oxidative phosphorylation). The overall goals of this project are to 1) identify novel regulators governing the endothelial epi-genomic, epi-transcriptomic, and metabolic responses to blood flow and 2) engineer innovative nanoparticles which target each of these pathways treating vascular complications in vivo. The scientific premise is that innovative nanoparticles can effectively deliver therapeutic nucleotides targeting these mechano-sensitive pathways in activated endothelium. This proposal addresses a significant knowledge gap in endothelial biology and an uncharted territory in vascular medicine, research directions being pursued by only a small number of laboratories world-wide. Our team has laid much the groundwork in developing multidisciplinary knowledge, technologies, and animal models necessary to investigate new endothelial mechanotransduction paradigms and moreover, devise precision nanomedicine strategies for future tailor-made vascular therapies. Successful completion of the proposal will establish a proof of concept of targeted nanomedicine in vascular wall-based therapies. The proposed studies should further preclinical development and eventual clinical testing of new therapeutic strategies to treat vascular diseases.

NIH Research Projects · FY 2025 · 2022-06

Summary. There is a dearth of information in any system about how developmental experiences have lasting influence on behavioral patterns. However, the multitude of examples of experiences directing typical, atypical, and therapeutic neurodevelopmental outcomes in humans and research animals indicates that the mechanisms by which experience-dependent plasticity modifies maturational programs in behaviorally-relevant brain circuits have broad implications. Why does our neurobiological understanding lag behind the behavioral evidence? Perhaps it is because linking juvenile experiences with adult behaviors requires a careful tracking of several timescales: from moment-to moment changes that occur rapidly with each relevant experience, to longer timeframes that take into account accumulated experiences, and the sustained backdrop of experience- independent maturational progression with which these experience-dependent changes intersect. No one measure or methodology can capture these dynamics. This is a large challenge, one that necessitates a research model that has strong, established experience-behavior links across development. The zebra finch songbird is such a model. In these birds, juvenile song experience has relevant and life-long consequences on adult patterns of social behavior in both males and females, in males, the structure of the song he sings his entire adult life and in females, her song and mate preferences; mate pairs stay together their entire lives. Song processing requires the higher-order association components of the auditory forebrain in males and females. Generally, it is obvious that epigenetic and molecular regulation of transcription and translation are at the core of neural plasticity, both maturational and experience-dependent, but it is not yet totally clear in any system how these mechanisms operate in concert to encode experiences during maturational stages such that they emerge as stable behaviors months and years later. Our published and preliminary data lead to our central hypothesis, that the specific mechanisms operating within the male and female juvenile auditory forebrain, while controlled by the same broad epigenetic and molecular regulatory processes, are distinct. To reduce the gap between observations of experience-behavior links and the mechanisms that mediate these connections, we have two current goals, 1) establish that adult behavior in both sexes is influenced by epigenetic and molecular processes as a result of accumulated and acute juvenile song experiences, 2) determine the extent to which specific mediators of cell structure and function are unique in juvenile male and female auditory forebrains. We will achieve these goals in three aims, which 1) test the role of histone H3 acetylation in gating the strength of juvenile song experiences on adult patterns of behavior and the regulatory transcription factors that may coordinate that link, 2) identify the “first wave” of epigenetic and molecular responses to hearing song that initiate neural remodeling, and 3) determine the extent to which molecular control of transcription and translation known to be necessary for adult behaviors differs by sex.

NIH Research Projects · FY 2026 · 2022-05

Abstract Cardiovascular disease is the leading global cause of death, accounting for more than 17.9 million deaths per year in 2015, a number that is expected to grow to more than 23.6 million by 2030. Several genetic and environmental factors contribute to cardiovascular disease risk. Bisphenol A and phthalates are two endocrine disruptors that are widely present in plastic and cosmetic products of daily use. These chemicals induce endothe- lial cell death and have been associated with increased risk for atherosclerosis and coronary artery disease. We propose to identify genetic variants that interact with BPA and phthalates and modify gene regulation in vascular cells, with consequences for cardiovascular health. We will use RNA-seq and ATAC-seq to characterize gene expression and chromatin accessibility changes induced by BPA and phthalates in vascular cells. We will focus on vascular endothelial and smooth muscle cells from African American donors, a population group at a higher risk of dying of preventable cardiovascular disease, compared to European Americans, but underrepresented in genetics and functional genomic studies. Using molecular QTL mapping approaches we will discover new gene- environment interactions for BPA and phthalates. We will then use computational predictions and statistical genetics approaches to fine-map these gene-environment interaction signals and colocalize them with associ- ation data for cardiovascular disease. Finally, we propose to use massively parallel reporter assays to validate these GxE in gene expression and deliver a catalog of functionally validated GxE risk factors for cardiovascular disease.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT Detecting adaptive genetic variation in population genomic datasets is important for understanding the genetic architecture underlying complex genetic diseases. Humans and other natural populations have been evolving under complex demographic histories, including divergence of ancestral populations, migration in structured populations, and past population size changes. Adaptive genetic variation and variation subject to complex demographic histories can result in similar observable genomic patterns, and distinguishing the evolutionary forces underlying genetic variation observed in natural population remains challenging. It is thus of importance to unravel the complex demographic histories underlying natural populations, and develop methods that detect adaptive genetic variation while properly accounting for these histories. In addition to contemporary genomic data, researchers have been gathering genetic data from ancient human remains in recent years. Including such datasets into the analyses has the potential to vastly improve our ability to detect population structure and genetic variation adapting to selective pressure. Thus, we will develop several tools for the analysis of contemporary and ancient genomic datasets to unravel the migration histories underlying the population expansion of humans and to detect adaptive genetic variation while accounting for these histories. To this end, we will develop a novel Coalescent Hidden Markov Model method to characterize complex migration histories. Our novel approach will use more efficient representations of local genealogies then previous approaches, which increases the accuracy of the inference and is more robust to noise in the data. Moreover, this framework will allow us to analyze population genomic data from large public databases to identify adaptive genetic variation. The local genealogies will be highly skewed in regions with adaptive genetic variation, as compared to genomic regions evolving under neutrality. The novel framework can be used to compute the posterior distribution of genealogical summaries at different locations in the genome to identify regions with skewed genealogies. In addition, we will implement approaches to detect adaptive genetic variation based on forward-in-time solutions of the dynamics of beneficial genetic variation and linked neutral regions. Based on a previously developed numerical approach, we will develop composite likelihood frameworks of observed genomic sequence variation under this model to detect adaptive genetic variation, while accounting for the underlying complex demographic history. Moreover, we will develop a method that aims at detecting polygenic adaptation from ancient DNA. This approach will be based on explicit likelihood models of the underlying allele frequency dynamics and allow us to detect and quantify directional and, unlike previous approaches, stabilizing selection on complex traits. Lastly, we will collaborate with colleagues to apply these methods and other appropriate tools to ancient DNA datasets to unravel the genetic response of medieval European populations to the Black Death pandemic.

NIH Research Projects · FY 2026 · 2022-04

Abstract Fewer than half of all children with high-risk neuroblastoma become long-term survivors. Currently, it is not possible to predict if a child will be cured with standard therapy or is destined to relapse. Furthermore, standard clinical evaluations lack sensitivity to detect minimal residual disease (MRD) that ultimately leads to recurrence. Thus, there is a critical challenge and an unmet need to develop new precision biomarkers to identify patients who will ultimately have a poor response to the high-intensity therapy and may benefit from alternate approaches. We will develop new biomarkers to guide treatment decisions using cell-free DNA (cfDNA) and a novel, epigenetic-based methodology that will identify underlying biology driving aggressive neuroblastoma. In many cancer types, analysis of cfDNA isolated from peripheral blood has shown promise, revealing biomarkers for diagnosis, prognostication, and tumor surveillance. Cytosines in DNA can either be unmodified, methylated (5- methylcytosine, 5mC), or contain an oxidized form of 5mC, 5-hydroxymethylcytosine (5hmC). Unlike 5mC, elevated 5hmC deposition across a gene body marks active transcription. In this proposal, we will use nano- hmC-seal, a whole-genome methodology for analyzing 5hmC modifications in cfDNA. Recently, we evaluated 5hmC in cfDNA collected serially from children with neuroblastoma and demonstrated that 5hmC profiles correlated with disease burden and patient outcome. Importantly, we also found a cfDNA 5hmC derived biomarker can distinguish patients with superior response to treatment from those at high risk for relapse. 5hmC profiles from cfDNA compared to diagnostic high-risk primary tumors demonstrated cfDNA is derived from clinically aggressive, malignant cells with activation of networks common in relapsed tumors. To prospectively determine the prognostic strength of 5hmC-based cfDNA biomarkers, we will use nano-hmC-seal to generate 5hmC profiles from clinically annotated serial blood samples (liquid biopsies) collected from 400 patients enrolled on the ongoing Children’s Oncology Group High-Risk Neuroblastoma Phase III study (ANBL1531, NCT03126916). We hypothesize that cfDNA 5hmC profiles from children with neuroblastoma will serve as superior biomarkers for response and survival compared to current clinical methods and will reveal transcriptional networks driving relapse. The specific aims are: 1) Evolve and validate biomarkers of poor response at diagnosis; 2) Prospectively identify minimal residual disease (MRD) and predict relapse from serial cfDNA 5hmC profiles; 3) Experimentally confirm candidate networks enriched in cfDNA at relapse. The success of this proposal will lead to: 1) unprecedented diagnostic biomarkers to improve therapeutic decisions; 2) early detection and interventions for patients with relapse causing MRD; 3) identification of epigenetic mechanisms which drive relapse. This work will have a transformative impact by to identifying patients who benefit from early introduction of alternate therapy, improving outcomes for those with aggressive disease.

NIH Research Projects · FY 2025 · 2022-04

PROJECT SUMMARY/ABSTRACT Deletions of all or part of chromosome 7 [-7/del(7q)] are among the most common karyotypic abnormalities in myeloid diseases, particularly high-risk myeloid diseases. Myelodysplastic syndrome (MDS) is a series of clonal disorders characterized by ineffective hematopoiesis, leading to peripheral cytopenias and dysplasia in one or more blood lineages with risk of transformation to acute leukemia. -7/del(7q) is found in 10% of adult MDS cases and, strikingly, in up to 50% of pediatric MDS cases. The presence of -7/del(7q) is associated with a poor karyotype and higher risk MDS, and carries a worse prognosis than cases with diploid chromosome 7. -7/del(7q) is often the only cytogenetic finding, and in a subset of pediatric MDS cases is the sole detectable molecular abnormality, strongly suggesting a driving role for chromosome 7 deletions in disease pathogenesis. There have been no new therapies for MDS in over a decade, highlighting an urgent need to better understand the recurrent genetic features of MDS that may lead to new treatment options. The lack of synteny between human and mouse chromosome 7 is a major barrier in the development of animal models of -7/del(7q). In a breakthrough in the field, our lab identified CUX1, a homeobox transcription factor shown to regulate cell proliferation and apoptosis, as a haploinsufficient myeloid tumor suppressor gene located in a commonly deleted region of 7q. Our lab engineered a doxycycline-inducible shRNA CUX1- knockdown mouse, and mice deficient in Cux1 develop a myeloid disease with trilineage dysplasia and lethal anemia, hallmarks of MDS. These data strongly support a role for this 7q-encoded gene in MDS etiology. However, chromosome 7 deletions are often large and span additional genes that alter hematopoiesis or lead to myeloid disease when deleted in mouse models. These data suggest 7q may be a contiguous gene syndrome region, in which loss of multiple neighboring genes en bloc contributes to disease development. Our preliminary data show CUX1 loss in human K562 leukemia cells decreases the repressive epigenetic histone mark H3K27me3. We further show that combined loss of Cux1 and the 7q gene Ezh2, an H3K27 methyltransferase, in murine hematopoietic progenitors synergistically increases myeloid cell expansion in vitro, compared to either gene alone. These data provide support for the hypothesis that 7q is a contiguous gene syndrome region. This proposal aims to: 1) leverage CRISPR-Cas9 gene editing to identify combinatorial 7q gene deletions that cooperate with Cux1 loss to drive del(7q) pathogenesis; and 2) define mechanisms by which loss of 7q genes drives del(7q) pathogenesis by characterizing the epigenetic and transcriptional landscape of cells deficient in Cux1 alone or with combined Ezh2 loss. This proposal will advance our understanding of chromosome 7 deletions and provide me with a specialized skill set in myeloid neoplasia and genomics that will propel me toward a career as an independent investigator.

NIH Research Projects · FY 2025 · 2022-04

Abstract The overall goal of this multi-principal investigator proposal is to facilitate the transition from implication of genetic variants identified in extensive genome wide association studies (GWAS) of Atrial Fibrillation (AF) to the molecular mechanisms underlying AF risk. We hypothesize that a novel genomic and analytic pipeline interrogating regulatory function of genetic variation will identify candidate causative variants and their target genes, enabling the transition from simple associations to causative mechanisms for the arrhythmia. In preliminary studies, we have applied novel single cell approaches to generate cell-type-resolved high-resolution chromosome accessibility maps and taken advantage of coordinated genomic signals to link AF risk variants to candidate causative AF genes. The results describe a highly interconnected gene regulatory network for cardiac atrial gene expression. In our first aim we propose to generate multi-modal single-cell genomics data to provide higher-resolution annotation of variant effects. We will improve our computational procedure to better leverage these datasets for AF variant and gene discovery. In our second aim, we will interrogate the interconnected gene regulatory network in molecular enhancer assays and genomic chromatin conformation capture experiments, to directly examine the impact of nominated genetic variants and their physical association with candidate target genes. In our third aim, we will examine the functionality of high confidence variant SNPs in depth, including their impact on gene regulation in cis, their impact on human cardiomyocyte electrophysiology, and their impact on cardiomyocyte gene expression and chromatin status in trans. We have established a tractable strategy that will help enable the transition from AF risk variants to molecular mechanisms. We anticipate that our approach will help translate the promise of AF genetics into meaningful biological insights for AF and establish a paradigm for the molecular understanding of genetic association studies in any system.

NIH Research Projects · FY 2026 · 2022-03

PROJECT ABSTRACT Dendritic cells (DCs) are immune sentinel cells that can be activated by innate stimuli to orchestrate adaptive immune responses. Conventional DCs (cDCs) efficiently present and cross-present antigens to prime T cell responses, whereas plasmacytoid DCs (pDCs) rapidly produce type I interferon (IFN-α/β, IFN-I) and other cytokines in response to pathogen-derived nucleic acids. Recent studies revealed an intricate topological organization of the genome into topologically associated domains (TADs) established through cohesin- mediated loop extrusion and demarcated by binding sites of transcription factor CTCF. CTCF/cohesin- mediated chromatin architecture is thought to control cell type-specific gene expression programs, thereby facilitating cell differentiation and function. However, the topological chromatin landscapes of DCs and their role in DC differentiation and function are poorly understood. The overall goal of the project is to characterize the chromatin architecture in DCs and elucidate the chromatin-level control of DC function. In Aim 1, we will examine the role of CTCF/cohesin-mediated regulation in the differentiation of DC subsets. In Aim 2, we will analyze the role of cohesin in DC function, including cytokine responses and antigen presentation. In Aim 3, we will analyze the architecture of the locus encoding IFN-I genes, and the role of chromatin in the control of interferon production in DCs. Collectively, these results would provide novel insights into the role and mechanism of chromosomal organization in the regulation of DC differentiation and function.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Atrial fibrillation (AF) is the most common heart rhythm disorder that affects >3 million Americans and is a major cause of stroke. Since AF is primarily an age-related disease, it is fast becoming an epidemic in a rapidly aging population. Unfortunately, current therapeutic approaches to AF – both pharmacological and ablation- based - are sub-optimal in patients with persistent AF. This is thought to be because current treatments do not target the fundamental, molecular mechanisms that cause AF. Over the last several years, the Arora lab at Northwestern University has worked hard to better understand the molecular mechanisms underlying AF, with the long term goal of developing a mechanism-guided therapeutic approach to AF. Work done in the Arora lab over the last several years in large animal models of AF has demonstrated that autonomic nervous system signaling, oxidative injury and CAMKII signaling are important mechanisms leading to electrical remodeling of key ion channels and excitation contraction coupling proteins in the atrium, thereby leading to the establishment of substrate for paroxysmal AF. The goal of the Arora lab over the next several years is to obtain a better understanding of the molecular mechanisms that underlie the progression of paroxysmal AF to persistent AF. We postulate that structural changes in the atrium such as new parasympathetic nerve sprouting, NLRP3 inflammasome mediated fibrosis and HDAC6 mediated breakdown of microtubules (derailed proteastasis) are key mechanisms underlying this progression of AF. We will study these mechanisms in chronically tachypaced large animal models of AF by using novel gene therapy approaches developed in our lab over the last several years. Success of these gene therapy approaches in arresting progression of paroxysmal AF to persistent AF will also demonstrate their therapeutic potential. Since our eventual goal is to develop a clinically viable gene therapy approach for persistent AF, we have recently conceived of a highly novel electroporation-based approach to facilitate trans-venous gene delivery. In addition to identifying novel gene therapy targets for AF, another major goal of this R35 proposal will be to fully develop and optimize this gene delivery approach. The next phase of the research proposed in the Arora lab is not only expected to give fresh mechanistic insights into the creation of an atrial myopathy that supports persistent AF, but is also expected to led to the development of new, potentially paradigm-shifting therapeutic approaches to AF.

NIH Research Projects · FY 2026 · 2022-02

Membrane traffic in the endomembrane system is well characterized at the level of components, but crucial aspects of the engineering logic of this system remain obscure. Definitions of endomembrane system compartments are often fuzzy, and knowledge of the directionalities and functions of membrane traffic pathways is incomplete. A particularly enigmatic organelle is the Golgi apparatus. Studies of yeast cells indicate that Golgi cisternae are transient, maturing structures, with resident Golgi proteins distributing in a polarized manner across cisternae of different ages. The Golgi recycles components internally and also communicates extensively with other endomembrane system organelles, but the links between membrane traffic and Golgi organization are poorly understood. We propose that the Golgi can be productively viewed as a set of maturing cisternae, with various membrane traffic pathways being switched on and off in an orderly way during cisternal maturation. Our goal is to elucidate these Golgi-associated membrane traffic pathways and to dissect the molecular logic circuit that controls them. We use budding yeasts as an experimental system. The secretory pathway in Saccharomyces cerevisiae has an unusual organization: non-stacked Golgi cisternae are scattered throughout the cytoplasm, and based on our recent work, the trans-Golgi network (TGN) serves as an early endosome. These properties simplify the analysis of individual maturing cisternae by 4D fluorescence microscopy. By determining the kinetic signatures of proteins as they arrive and depart during cisternal maturation in wild-type or mutant cells, we can obtain novel insights. Recent discoveries include: (1) COPI vesicles mediate recycling of early but not late Golgi proteins. (2) The AP-1 clathrin adaptor is restricted in yeast to the TGN. This result, taken together with prior work from other groups, implies that AP-1 mediates intra-Golgi recycling downstream of COPI. (3) As revealed by our development of a regulatable fluorescent secretory cargo that can be visualized in maturing cisternae, AP-1 has an unexpected ability to promote intra-Golgi recycling of this secretory cargo. (4) In unpublished work, AP-1 cooperates with the clathrin adaptor Ent5 to drive two sequential pathways of intra-Golgi recycling. Transmembrane proteins that recycle by the various COPI- or AP-1-dependent pathways become concentrated in different cisternae, thereby creating the polarized distribution of proteins across the Golgi. Our ongoing efforts with S. cerevisiae are aimed at a molecular characterization of these membrane traffic pathways. We plan to assign roles in specific pathways to individual vesicle tethers, SNAREs, and lipid metabolism processes. In addition, we will identify functional connections that coordinate the timing of the different pathways. A newer project employs cultured mammalian cells. We will use imaging and genome editing to revisit three phenomena that are seemingly at odds with the cisternal maturation concept: nonlinear cargo exit from the Golgi, exchange of secretory cargoes between Golgi ribbons, and retention of aberrant proteins in the TGN. Those phenomena can potentially all be explained by a conserved pathway involving AP-1-dependent recycling of secretory cargoes. Our ambition is to achieve a unified understanding of how the secretory pathway operates in both yeast and mammalian cells.

NIH Research Projects · FY 2026 · 2022-02

The proposed research will test related hypotheses that thalamus plays a heretofore neglected and critical role in cortical processing. In particular, many thalamic nuclei, that together comprise the majority of thalamic volume and that were previously mysterious in function, we now suggest are critically involved in information flow and functional, dynamic binding between cortical areas via cortico-thalamo-cortical pathways. We propose to study these pathways using the mouse somatosensory system as the model involving both in vitro slice preparations and an in vivo behaving preparation. It appears that, in many and perhaps all cases, cortical areas are connected by both direct and these transthalamic pathways. The transthalamic pathways are only recently appreciated, and we aim to explore some basic roles such pathways play in cortical processing. To begin understanding the role of such pathways, we propose to probe basic circuit properties of these pathways to better understand the role of the transthalamic pathways in higher cognitive functioning.

NIH Research Projects · FY 2026 · 2022-01

PROJECT SUMMARY Brain-Computer Interfaces (BCIs) have achieved remarkable progress over the last decade, including the direct control of sophisticated anthropomorphic robotic arms and the incorporation of tactile feedback. However, the dexterity of current brain-controlled prosthetic limbs is limited in two important ways. First, most neuroprosthetic control involves decoding kinematics from the responses of neurons in primary motor cortex (M1). While this approach has been successful for controlling the proximal arm (shoulder and elbow) to place and orient the hand, it is fundamentally inadequate for hand control and interactions with objects, which requires not only orienting the wrist and shaping the digits but also applying appropriate forces. This problem is complicated by the fact that force and kinematic signals as well as hand and arm signals are all intermingled in the neural population activity in M1. Furthermore, hand and arm representations of force and kinematics seem to depend on the task, as evidenced by the fact that decoders developed for one task fail to generalize to another. Second, tactile feedback is critical to manual behavior as evidenced by the severe deficits that result from deafferentation. To achieve dexterous control of a prosthetic arm thus also requires restoration of tactile feedback. One promising approach is intracortical microstimulation (ICMS) of somatosensory cortex (S1), which evokes vivid tactile percepts experienced on the (otherwise insensate) hand. There is a growing consensus that mimicking naturalistic patterns of neuronal activation will lead to more natural tactile percepts and more dexterous hand use. However, the neural basis of touch has been studied almost exclusively with stimuli passively presented to the unmoving hand, which precludes any understanding of how motor behavior shapes S1 responses and hinders the development of biomimetic encoding algorithms. To fill these gaps, we will have NHPs perform prehensile behaviors in which we systematically vary hand and arm kinematics and forces, and measure the time-varying postures of the entire limb and the forces exerted on objects, including contact forces at each digit. We seek to characterize (1) signals in M1 relating to kinematics and forces exerted by the arm and hand; (2) signals in S1 relating to active interactions with objects; and (3) signals transferred between M1 and S1. We propose to apply well-established encoding and decoding techniques to investigate the relationship between neural responses and movement parameters as well as a novel dynamical systems analysis. The resulting insights into the neural mechanisms of prehension will lead to (1) the development of decoders of intended limb state from M1 responses that include both kinematics and force control and generalize across behavioral tasks; (2) biomimetic sensory encoding algorithms informed by an understanding of active touch representations in S1. The research team is uniquely poised to test the resulting decoders and sensory encoding algorithms in human BCI participants as part an ongoing clinical trial at both sites through an ongoing NIH funded project.

NIH Research Projects · FY 2026 · 2022-01

Project Summary In a professional table tennis rally, the time between successive ping pong ball hits is around 400ms. Within this timeframe, the players must rapidly categorize the motion and spin of the ball to appropriately guide the ongoing motion of their paddle to successfully strike the ball. While numerous studies have investigated the oculomotor system’s role in the visual categorization process, few have done so where the response must be initiated in advance of relevant sensory information, such as in the aforementioned example. Thus, the temporal dynamics of sensory modulation of saccadic decisions remain largely unresolved. To identify the manner in which visual categorization informs ongoing motor plans, I propose recording neural activity from populations of neurons in the lateral intraparietal area (LIP), frontal eye field (FEF), and superior colliculus (SC) while monkeys perform a saccade-based motion categorization task in which motor planning always precedes the identification of the visual stimulus; consequently revealing the temporal evolution of a categorical judgment with millisecond resolution. Results from prior studies identified neurons in LIP and FEF that demonstrate categorical tuning, with increased firing rates when stimuli belonging to the preferred category appear on screen. Additionally, a recent study from our lab demonstrates the causal role of LIP in visual categorization in which reversible inactivation of LIP leads to significant deficits in categorization accuracy. However, the task structure utilized by these studies precludes any attempt to uncover the manner in which categorical signals influence ongoing motor plans, or identify differences in the timing and strength of categorical encoding between these brain regions. To date, no study has investigated categorical encoding in SC, thus we will be the first to identify its role in visual categorization. By simultaneously recording from large, diverse populations of neurons with linear arrays across these interconnected brain regions, the proposed research will provide critical insight into the temporal dynamics underlying the transformation of sensory evidence into oculomotor decisions.

NIH Research Projects · FY 2025 · 2022-01

Project Summary/Abstract Potassium channels are membrane proteins critical for the electrochemical regulation and function of cardiac cells. Many diseases are associated with mutations in human potassium channels, including Long-QT Syndrome, Short-QT Syndrome, Brugada Syndrome, Lev-Lenegre Syndrome, and Idiopathic Ventricular Fibrillation. The molecular basis of these diseases remains poorly understood, and many arrhythmia-associated mutations may directly disrupt protein folding. Therefore, it is essential to study the mechanism and biophysical determinants of potassium channel folding to understand how these mutations may result in arrhythmia. Preliminary work is presented here on the in vitro folding of the KcsA transmembrane pore domain, a robust model system for human potassium channels such as hERG and Kv1.2. This work suggests that KcsA rapidly inserts as monomers into a protein-dense region within the lipid membrane, and tetramerization kinetics are protein concentration-independent, implying a unimolecular rate-limiting step despite the tetrameric nature of the channel. These observations raise the following questions: What is the role of the protein-dense region in potassium channel folding? What are the structural events in potassium channel folding, specifically regarding the rate-limiting step? Lastly, and most relevant to cardiac health, how might missense mutations of the pore helix, such as A614V, L615V, and T623I of hERG, disrupt folding and lead to arrhythmia? The proposed work will investigate the protein-dense region using super-resolution light and scanning-probe microscopy in reconstituted membranes and live HL-1 cardiomyocytes to evaluate the hypothesis that the protein-dense region functions to quickly concentrate channel monomers in the membrane and thus increase the speed and efficiency of folding. To determine the structural events in channel folding, we will use a novel hydrogen-exchange mass spectrometry (HXMS) technique alongside other biophysical methods to evaluate the hypothesis that folding must occur by one of two possible mechanisms: (1) a “native assembly model” in which four natively-folded channel monomers assemble in a single, concerted step, or (2) a “keystone model” in which the transmembrane helices of each monomer initially tetramerize into a transmembrane bundle, and then the pore helix and selectivity filters insert into and stabilize the channel like the keystone of an arch. Pulse-labeling and native state HXMS will probe the folding dynamics and stability, respectively, of channel variants associated with Long-QT Syndrome to evaluate the hypothesis that pore helix missense mutations can cause disease by preventing proper pore helix folding. These approaches will be complemented by computational coarse-grained and all- atom techniques, including a novel “committor” analysis method to study the reactive flux between metastable folded and unfolded potassium channel states. The proposed work is high impact: It uses innovative and interdisciplinary techniques such as HXMS to uncover the mechanism of potassium channel folding and its implications for cardiac arrhythmia. These insights will inform future studies of membrane protein folding biophysics as well as the pathogenesis of heart rhythm disorders.

NIH Research Projects · FY 2025 · 2022-01

ABSTRACT The Dynamic Experiences in Neuroscience to Diversify Research Internship Training Exposures for Students (DENDRITES) Program aims to encourage and support the research and career development of underrepresented minorities (URM) students interested in basic, clinical, and translational neuroscience. The DENDRITES Program will accomplish this by executing three specific aims. The first aim is to expose undergraduate students to an intensive nine-week mentored summer research experience by pairing students with an experienced scientific mentor that will introduce students to robust and rigorous research experiences. The goal is for URM undergraduate students to get hands-on research experience which will expose them to cutting-edge neuroscience research and solidify the students’ commitment to research careers. The second aim is to leverage the Leadership Alliance Summer Research – Early Identification Program (SR-EIP) at UChicago to facilitate the transition to graduate programs. To accomplish this aim, we will collaborate with the SR-EIP to offer professional development workshops which will improve DENDRITES participants’ skills and qualifications to make them competitive candidates when applying for graduate school. In addition, we have created unique activities for DENDRITES participants such as cluster groups meetings and a seminar series led by graduate students. These activities will provide educational resources and experiences which visiting URM students would otherwise not receive at their home institutions. Finally, by collaborating with the University of Chicago SR-EIP program DENDRITES participants will be able to attend the Leadership Alliance National Symposium which will allow students to present and disseminate their summer research. The third aim is to recruit students historically underrepresented in academia to diversify the neuroscience workforce. By familiarizing students with UChicago, its opportunities, and its faculty members, our program will facilitate students’ later application and potential acceptance into highly-competitive graduate schools. Overall, the long- term goal of the DENDRITES Program is to diversify the neuroscience workforce by creating a strong pipeline of young neuroscience researchers who can make significant contributions to neuroscience discoveries.

NIH Research Projects · FY 2025 · 2022-01

ABSTRACT The normal aortic valve is tricuspid with three leaflets derived from multiple cell lineages during embryogenesis. Aortic valve patterning is genetically controlled where individual cells in the valve- forming field refine their fates and functions in response to positional and environmental cues. Genetic mutations that alter cell-cell and cell-environmental signals can disrupt the developmental process, leading to anomalous aortic valve, for example, bicuspid aortic valve (BAV). Affecting ~2% of the general population in US, BAV is the most common congenital heart defect. Fusion of two of three leaflets or absence of one leaflet during embryogenesis results in various BAV subtypes. After birth, over half of BAV patients develop calcific aortic valve disease with no effective medicine, while BAV subtypes have varied cardiac complications, which decide the disease outcome. With the International Bicuspid Aortic Valve Consortium (BAVCon) being established to identify the genetic causes of BAV in humans, animal models of BAV are critically needed to elucidate morphogenic and cellular mechanisms of human BAV, as well as molecular signals that control aortic valve patterning in order to identify therapeutic targets for disease prevention. To this end, we have generated two mouse models of BAV with distinct signaling defects and anomalous leaflets. In the first model, knocking out notch receptor 1 (Notch1) in valve endocardial cells (VECs) recapitulates the most common human BAV subtype – fusion of left and right coronary leaflets, which are mainly derived from VECs by epithelial to mesenchymal transformation. This model also reveals that the NOTCH1- TNFa signaling from VECs controls apoptosis of valve mesenchymal cells (VMCs). In the second model, deleting SRY-box transcription factor 17 (Sox17) in VECs results in a rare but more severe type of BAV – absence of non-coronary leaflet, of which VMCs arise predominantly from the second heart field (SHF)-derived cardiomyocytes, and the patterning defect is associated with reduced VEC-VMC PDGFB signaling. Based on these findings, we hypothesize that coordinated VEC-VMC signals control normal aortic valve patterning and their disruption leads to various BAV subtypes, in the context of the origin and location of affected cells. We will test this hypothesis in two Aims. Aim 1 is planned to reveal coordinated VEC-VMC signal networks during normal aortic valve patterning and identify signaling events that are disrupted in various BAV subtypes. Aim 2 is designed to uncover the functions of PDGF signaling in normal aortic valve patterning as well as use it as an example to illustrate how a disrupted signaling event can alters cell fate and function, leading to a specific BAV. Successful accomplishment of these Aims will provide new insights into BAV pathogenesis, with a broad implication in congenital heart valve disease.

NIH Research Projects · FY 2026 · 2022-01

Project Summary A conceptual and empirical revolution is occurring in our understanding of the eukaryotic heat-shock response. Heat shock has long been conceived of as a proteotoxic stress, triggering formation of toxic aggregates of denatured proteins, which must be cleaned up by induced heat shock proteins. Recent results from our group and others have established a complementary paradigm: temperature acts as a physiological signal, triggering the adaptive formation of biomolecular condensates with specific cellular functions, and the condensation process is regulated by heat shock proteins. Crucially, in the proteotoxic model, aggregates are trash, but in the adaptive condensation model, they are functional treasure. Using an integrated set of biochemical, cell biological, and evolutionary approaches established over the past decade, we are pursuing three linked areas: 1) identifying and dissecting the cellular functions of particular heat-shock and stress-induced condensates of protein and mRNA; 2) studying the regulation of condensation and dispersal, focusing on the specificity of physiological condensates and their remodeling and reversal by stress-induced molecular chaperones; and 3) probing the sensation and transduction of temperature into adaptive responses in fungi which rely on warm-blooded hosts for growth or dispersal, and in the temperature-dependent activation of cells in the vertebrate immune system during fever. In addition to fundamental insights into the operation and organization of eukaryotic cells, these studies promise to shed light on intracellular aggregation processes known to be dysregulated during neurodegenerative disease, uncover new mechanisms for the control of fungi, and provide new molecular insight into how fever promotes immune-cell activation.

NIH Research Projects · FY 2025 · 2021-12

Project Summary RNA chemical modifications, collectively referred to as the “epitranscriptome”, have recently emerged as a novel layer of molecular control of gene expression. Most epitranscriptomic studies address N6- methyladenosine (m6A) of mRNA in human cancers. The molecular identity of endothelial mRNA epitranscriptome and its potential role in regulating vascular functions remains a major knowledge gap. Recent studies suggested that mammalian mRNAs are broadly chemically modified and mRNA modifications occur in a cell-type and cell-state dependent manner. N6-methyladenosine (m6A), the most abundant internal (outside of the 5’ cap) methylation in mammalian mRNA, has been linked to critical biological processes such as proliferation, development, and stem cell differentiation. Only few recent studies addressed the potential role of mRNA m6A in cardiomyocyte remodeling and endothelial activation. We recently discovered the presence of a new chemical modification, N7-methylguanosine (m7G) in mammalian mRNA. Systematic m7G mapping in endothelial mRNA and its potential role in vascular pathophysiology is an unexplored territory. Vascular endothelium is dynamically regulated by blood flow via mechano-transduction mechanisms. Endothelial activation by disturbed flow contributes to a wide range of vascular diseases. Atherosclerosis preferentially develops in arterial sites where endothelium is activated by local disturbed flow whereas unidirectional flow promotes endothelial health. Current atherosclerosis therapies mainly target systematic risk factors but not the vasculature per se. This underscores the significance and unique opportunity to identify and target novel mechanosensitive mechanisms in vascular endothelium. We have generated very strong data demonstrating that the mRNA m7G is dynamically regulated in endothelium by hemodynamics. Unidirectional flow (UF) markedly increases m7G but not m6A in endothelial mRNAs. Moreover, Methyltransferase-Like 7A (METTL7A) is a novel m7G writer governing the UF-induced mRNA m7G methylation in endothelium. The overall goal of this project is to delineate the novel molecular mechanisms by which mechano-sensitive METTL7A governs endothelial mRNA m7G and regulates vascular functions in vitro and in vivo. Moreover, we will devise innovative precision nanomedicine approaches targeting METTL7A-mediated pathways to treat atherosclerosis.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT Intestinal diseases, including inflammatory bowel disease (IBD), celiac disease, and infectious colitis are associated with epithelial barrier dysfunction that contribute to diarrhea and nutrient malabsorption. Tight junctions seal spaces between epithelial cells and maintain barrier function by controlling paracellular flux. The claudin family of tight junction proteins is critical in defining the tight junction barrier to ions and small molecules. In the gastrointestinal tract, claudin-2 and -15 are particularly important in their role regulating paracellular sodium flux and their altered expression can contribute to intestinal disease development. Using a novel patch clamp technique, we demonstrated that claudin-2 and -15 form gated Na+ selective ion channels in the paracellular space. This is important because it demonstrates that claudins have properties similar to transmembrane ion channels. However, we have limited understanding of how these cation selective claudins contribute to charge and size selective paracellular pores, how these two claudins function singly or together to impact intestinal function, and how they impact disease processes. To address these questions, we built all-atom computer models for claudin-2 and -15 which allowed us to model both claudin structure and pore function. These models also helped us to identify several first-in-class claudin channel blockers that block the pore at low micromolar concentrations. We propose to use these unique and novel computational and small molecule inhibitor tools to investigate how claudin-2 and -15 channels control monovalent cation flux across the tight junction, and how they may differentially regulate cation transport in health and disease. In Aim 1, we will use our claudin-2 and -15 computer models and channel blockers to determine key molecular and structural features that dictate size and charge selectivity. In Aim 2, we will use our existing and new claudin channel blockers to define the individual and combined contributions of claudin-2 and -15 to normal intestinal physiology and disease presentation and development. We will determine the role of claudin-2 and -15 channels in Na+-coupled nutrient co-transport- mediated barrier regulation, mouse models of colitis, and in human IBD. Completion of this line of study is expected to contribute positively to human health by providing key insight into how these channels mediate nutrient absorption, contribute to diarrhea in the setting of colitis, and potentially aid in the development of novel therapies.

NIH Research Projects · FY 2025 · 2021-09

The designation of SuperAger is reserved for individuals at or above the age of 80 who are not just free of cognitive impairment but who also have memory capacity that would be considered average for those 2-3 decades younger1, 2. It appears that SuperAgers may be resistant to the emergence of involutional cellular changes in the brain and/or resilient to their impact on cognition1-8. The importance of identifying biologic factors that drive SuperAging is self-evident. One obstacle has been the relative rarity of this phenotype and the necessity to establish a broad-based recruitment mechanism. In order to address this goal, and in response to RFA-AG-21-015, this proposal aims to establish a multicenter SuperAging Consortium to identify behavioral, health, biologic, genetic, environmental, psychosocial, anatomic, and neuropathologic factors associated with SuperAging. These goals will be achieved through an organizational structure with 3 Cores (Administrative/Biostatistics, Clinical/Imaging, and Biospecimen/Neuropathology), which will enroll 500 SuperAgers and Cognitively Average Elderly Controls through 5 Sites across the United States and Canada. The Consortium will build upon the strengths of exciting discoveries on the anatomy, biology and neuropsychology of SuperAgers identified through the NIA-funded SuperAging Program (R01AG067781), recruit an expanded cohort to consolidate preliminary results, launch new fields of inquiry, and increase the scope of the research with its emphasis on higher enrollment. To this end, the NIA-R01-funded SuperAging Program will join efforts with recruitment Sites in Ann Arbor, Atlanta, Madison, and Southwest Ontario, each of which was selected because of proven leadership and expertise in aging and dementia research. The SuperAging Consortium will leverage existing infrastructure at each of the Sites, including NIA-funded Alzheimer’s Disease Research Centers, the Ontario Brain Institute, and the NIA-R01-funded SuperAging Program. In addition to the creation of a unique and uniform cohort that will be curated for intramural and extramural collaborations, the Consortium will also include two major Research Projects that will address entirely novel aspects of SuperAging through real-time measurements of psychophysiological parameters and the genetic characterization of immune mechanisms. The SuperAging Consortium leadership includes investigators with expertise in successful cognitive aging and dementia, behavioral neurology, neuropsychology, digital biomarkers, neuroimaging,and neuropathology. Below we outline the critical anchor points of the SuperAging Consortium.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY/ABSTRACT This proposal seeks support for an MD/PhD Program in Medicine, the Social Sciences, and Alzheimer’s Disease and Related Dementias (AD/ADRD) centered at the University of Chicago (UC) in partnership with Rush University (RU). The program builds on strengths at the two institutions in Alzheimer’s disease and related dementias (AD/ADRD), the social sciences, and interdisciplinary research and its integration into the professions, including the training of MD/PhD students with PhDs in the Social Sciences. The proposed program will produce MD/PhD graduates trained in medicine, a social science or related profession (Economics, Sociology, Psychology, Comparative Human Development, Public Health Sciences, Business, Public Policy, and Social Work), and interdisciplinary approaches to aging research with a focus on AD/ADRD. AD/ADRD research training areas will include the epidemiology of AD/ADRD; the content, organization, and financing of care for persons with dementia; behavioral, health system and community interventions aimed at the prevention, early identification, and treatment of AD/ADRD; the care workforce and roles of formal and informal caregivers in health outcomes for persons with AD/ADRD; and methodological issues prominent in AD/ADRD research. The proposed approach to training builds on UC’s 30-year history of national leadership in training MD/PhDs in the social sciences through the Medicine, Social Sciences and Humanities (MeSH) program. UC’s training record has been exceptional, training more MD/PhDs in the social sciences than any other institution with exceptional placement and scientific impact in aging and AD/ADRD research. MD/PhD applicants will be able to apply to the program through one of three tracks: 1) the Pritzker School of Medicine Track, in which students apply simultaneously to the MD and PhD programs at UC; 2) the Rush Medical College (RMC) Track, in which students apply simultaneously to the MD program at RMC and PhD programs at UC; 3) the National Track, in which students at any U.S. medical school may apply to PhD programs at UChicago. The proposed program also benefits from the exceptional clinical and research expertise at RU in AD/ADRD, and RU’s participation expands local medical school options for trainees interested in research careers in AD/ADRD and earning a social science PhD from UC. The National Track pathway will also continue to further expand the pool of potential candidates eligible for the program by recruiting students from across the U.S., which we expect to especially help in expanding recruitment of minority trainees. Institutional support will allow us to matriculate 3 PSOM or RMC track students and at least 3 National Track students over the course of the award. Trainees’ focus on AD/ADRD research will be enhanced by their participation in relevant coursework, clinical experiences, and seminars in which they present their work to their colleagues and program leaders.Each trainee will be supervised by an interdisciplinary mentorship team including at least 1 MD/PhD in the Social Sciences, 1 NIA-funded AD/ADRD researcher, and 1 practicing geriatrician.