University Of Chicago

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY The Hedgehog (Hh) singling pathway orchestrates organ development, but its precise timing remains unclear. This project investigates whether Hh acts as a "heterochronic switch," controlling differentiation timing across organs. We aim to decipher the heterochronic switch role of Hh singling in lung development and potential contribution to two major lung diseases (COPD and IPF). Using a robust computational pipeline, we will analyze existing single-cell data from mouse and human lungs with three specific aims: 1) Deciphering Hh's temporal control: We'll analyze existing mouse datasets to understand how altered Hh impacts differentiation in both loss-of- function and gain-of-function scenarios. 2) Unveiling human lung dynamics: We will classify, track, and characterize Hh-receiving cells across fetal and adult lungs, comparing them to reveal changes in Hh timing control during development. And 3) Connecting Hh to disease: We will assess the impact of altered Hh signaling on lineage-specific cell populations in COPD and IPF, identifying disease-specific Hh target genes for further investigation. This proposed computational work could assess whether and how Hh acts as a differentiation timing control on lung progenitors, in normal development and disease. The impacts of this project include: (1) the first quantification of Hh's role in regulating lung differentiation timing; (2) a set of disease- and lineage-specific Hh target genes, potentially leading to new therapeutic strategies, and (3) a validated pipeline for studying heterochronic control in other organs. Therefore, success of this project can enhance our understanding of organ regeneration and disease pathogenesis. Beyond lung diseases, this project could potentially illuminate Hh's heterochronic role in various organs and diseases, paving the way for novel diagnostic and therapeutic approaches.

NIH Research Projects · FY 2026 · 2025-02

Summary and Relevance of Proposed Research Humans have a remarkable capacity to learn to recognize and make decisions about incoming visual stimuli. This ability, which is disrupted by brain-based diseases and conditions such as Alzheimer’s disease, schizophrenia, stroke, and attention deficit disorder, is critical because it allows us to learn about the meaning of the stimuli that we encounter, and it enables us to make appropriate decisions. The neuronal computations which underlie rapid and flexible visually-based decisions involve interactions among neuronal populations both within and between brain regions spanning visual, cognitive, and motor areas. To understand how coordinated neuronal activity mediated decision related neuronal computations, this project employs a close interaction between experimental and theoretical modeling approaches. The experimental work employs large- scale neuronal population recording techniques to monitor the activity in three interconnected brain regions— posterior parietal cortex (PPC), frontal eye field (FEF), and superior colliculus (SC)—during visual decision making tasks. Experiments also employ reversible inactivation of each brain region to causally test hypotheses. The theoretical work develops novel theories of neuronal population function directly inspired by the experimental data and inactivation results, in order to determine the patterns of neuronal activity and interactions within and between regions which support computations underlying task performance. While much is known about how the brain processes visual features (such as color, orientation, and direction of motion), less is known about how the brain learns and represents the meaning, or category, of stimuli. A greater understanding of visual categorization is critical for addressing many brain diseases and conditions (e.g. stroke, Alzheimer’s disease, attention deficit disorder, schizophrenia, and stroke) that leave patients impaired in everyday tasks that require visual learning, recognition and/or evaluating and responding appropriately to sensory information. The long-term goal of this project is to guide the next generation of treatments for these brain-based diseases and disorders by helping to develop a detailed understanding of the brain mechanisms that underlie learning, memory and recognition. These studies also have relevance for understanding and addressing learning disabilities, such as attention deficit disorder and dyslexia, which affect a substantial fraction of school age children and young adults. Thus, a detailed understanding of the basic brain mechanisms of categorical decisions and attention will likely give important insights into the causes and potential treatments for disorders involving these cognitive and perceptual abilities.

NIH Research Projects · FY 2026 · 2025-02

Project Summary: Natural killer (NK) cells exist in a chronically “primed” state that facilitates rapid cytokine production, chemokine-mediated dendritic cell and macrophage recruitment, and direct target elimination. These cells play a pivotal role in protection against -herpesviruses and coronaviruses, and in the immune response against metastatic tumors and leukemia. Emerging evidence supports an important role for NK cells in the initiation of the immune response against some solid tumors. While NK cell survival and function can be suppressed in the tumor microenvironment, these cells can be restored by environmental manipulation or checkpoint blockade therapy. These findings raise the possibility that NK cells, if manipulated appropriately, could have therapeutic benefits in multiple disease contexts including in solid tumors. Therefore, a comprehensive understanding of the mechanisms controlling NK cell survival, proliferation, and effector function in different disease contexts is needed. In this grant, we present preliminary data identifying BATF as a transcription factor induced by the proinflammatory cytokine IL-12, which is responsible for the priming of NK cells during their development and for NK cell expansion in response to viral infection. We will test the consequences of altered BATF expression, both loss and gain of function, on NK cell maturation and anti-tumor immunity (Aim 1) and the NK cell response to viral infection (Aim 2). We propose a comprehensive characterization of BATF target genes and the impact of BATF on chromatin accessibility, histone modification, and functional output. Taken together, these studies will provide a broad view of the requirements for BATF and the potential for modulating BATF or its target genes for therapeutic intervention in anti-viral and anti-tumor immune responses.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Infectious diseases have always been a major health problem throughout the world, imposing a strong selective pressure on the human genome. Despite the recent advent of vaccines and antibiotics, infectious diseases cause nearly 15 million deaths every year. Although a significant proportion of inter-individual variation in susceptibility to microbes can be attributed to environmental factors, a substantial portion is also due to host genetic factors. The importance of host genetic factors on susceptibility to infectious diseases has been shown by comparative studies involving twins and adopted persons. Yet, very little is known about the underlying genetic factors contributing to differences in susceptibility to infectious diseases at the population level. In addition, the level of epigenetic variation across individuals and populations, and how such variations might impact susceptibility to infectious agents remains unknown. By combining expertise in functional genomics, computational biology, human immunology, population genetics, and infectious diseases, we aim to identify genes and regulatory pathways that contribute to variability of immune response to two of the deadliest infectious agents of our days: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, and influenza virus. Specifically, we propose to leverage the power of induced pluripotent stem cells (iPSC)-derived macrophages to: (i) characterize inter-individual and inter-population variability in immune responses to infection with (Mtb) and influenza viruses in humans; (ii) study the contribution of epigenetic variation to inter-individual variation in immune responses; and (iii) map quantitative trait loci (QTL) that are associated with variation in the immune response to infection with Mtb and influenza, and evaluate the impact of natural selection at shaping their allele frequencies across populations. This work will yield unprecedented insight into the genetic and epigenetic basis underlying inter-individual variation in immune responses to two of the deadliest infectious agents of our days. Combined, these efforts will establish innovative, novel, and empirically grounded "immune profiling" strategies for identifying those most at risk for infectious diseases and other immune-related disorders, which together constitute one of the largest health burdens facing modern human populations.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Bacterial cholesterol-dependent cytolysins (CDCs) constitute the largest group of pore-forming toxins and serve as critical virulence factors for a wide variety of pathogenic bacteria. A number of CDCs are known to activate the NLRP3 inflammasome, a multiprotein innate immune signaling complex responsible for induction of proinflammatory cytokines (e.g., IL-1β and IL-18) and the proinflammatory cell death pyroptosis. Inhibition of NLRP3 inflammasome has been shown to significantly affect bacterial dissemination and pathogenesis. However, the detailed molecular and cellular mechanism underlying CDC-mediated inflammasome activation has not been fully characterized. In this proposal, we propose that CDCs can be grouped into two types based on whether they can directly remodel host organelle to stimulate the NLRP3 inflammasome signaling. This helps the host organisms clear invading bacteria, although excessive inflammation may also result in pathogenesis. Using a combination of SunTag live cell imaging, mass spectrometry analysis and infection models, we aim to define the motifs and host factors responsible for CDCs to reorganize host organelle and activate the NLRP3 inflammasome. We will also determine and characterize the abilities of Type II CDCs to escape the inflammasome activation via inhibition of host organelle remodeling. Our proposed studies will help define this host organelle remodeling activity of bacterial CDCs as potential broad-spectrum therapeutic targets to mitigate a wide range of infectious diseases.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY The adaptive immune response underpins protection against influenza virus infection, and strengthening the response is the goal of vaccination. However, we lack a good understanding of what factors determine a strong adaptive immune response to vaccination, particularly in individuals with prior exposure to influenza virus. The goals of the proposed study are to describe conditions under which strong, durable, and broadly protective adaptive immune responses to influenza arise and to use mechanistic and statistical models to understand precisely how these responses change over time, especially in response to vaccination. We will begin by identifying adults with “good” (strong, durable, and broad) and less good (transient, narrow, and/or weak) B and T cell responses in a randomized, placebo-controlled trial of repeat influenza vaccination. Participants will have received the recombinant influenza vaccine Flublok one to four years in a row, while a control group will not be vaccinated until year five. In the first phase of the proposed study, we will investigate participants’ antibody neutralization landscapes and B and T cell repertoires and ask how infections, vaccinations, and individual- specific factors shape the strength, durability, and breadth of the response, focusing on neutralizing antibodies and T cell phenotypes that we and others have identified as correlates of protection. Our statistical and mechanistic models will assess how exposures shape the evolution of B and T cell clones and the relationship between B and T cell repertoires and the specificity of the serum neutralizing antibodies. We will also investigate how B and T cell phenotypes, including their transcriptomes, relate to repertoire dynamics and the qualities of serum antibody and T cell responses. We will re-assess correlates of protection from infection. These foundational models will test many mechanistic hypotheses and involve exploration, including the use of machine learning for prediction. Consequently, in the next phase of the study, we will use a distinct observational cohort that includes vaccinated and unvaccinated participants from a wider age range to cross-validate our leading models and hypotheses, including correlates of protection. This approach should increase the robustness of the conclusions and deliver a set of statistical and mechanistic approaches that describe conditions leading to different responses to vaccination, predict B and T cell repertoire changes in response to influenza exposures, estimate multidimensional correlates of protection, and infer the dynamics of the adaptive immune response to influenza in individuals over time to understand in detail how variable vaccine responses arise. Our data and software will be findable, accessible, interoperable, and reusable (FAIR) to maximize their utility for other researchers investigating the evolution of adaptive immunity to influenza and other pathogens.

NIH Research Projects · FY 2026 · 2025-01

Project Summary The Rust Lab seeks to understand the biophysical basis of circadian rhythms and how they are connected to metabolism to support health and fitness. To do this, we are leveraging the power of a bacterial model system where the circadian clock functions cell autonomously and the core oscillator can be reconstituted in a test tube. We use a combination of live cell microscopy, protein biochemistry, and deep sequencing approaches to interrogate this system. The ultimate goal of this research program is to understand quantitatively the relationship between the circadian clock and the external environment that is required for fitness and to be able to recreate an oscillatory system that has these properties using purified components. During the award period, we plan to build on our previous discoveries linking clock control of glycogen metabolism, protein solubility, and DNA replication to understand how an appropriately timed metabolic switch allows cells to tolerate cycling environments. To do this, we are creating new technologies that will enable new assays. We will extend existing protein reconstitution systems using computer-controlled liquid handling to create oscillators that mimic protein synthesis and degradation characteristic of growing cells. We are developing live cell fluorescence reporters of glycogen metabolism. Finally, we will unleash the power of deep scanning mutagenesis and high-throughput sequencing on circadian clocks by creating saturating point mutant libraries of clock genes. We will determine the oscillator phenotype of each mutation as well as its fitness in cycling environments. This will provide an unprecedented view of the mutational plasticity of the circadian rhythm, the molecular determinants of the rhythm, and the selective pressures on the clock.

NSF Awards · FY 2025 · 2025-01

As urban contexts are changed by migration, redevelopment, and new technologies, residents are responding with complex forms of financial speculation that are oriented both to historically salient features of those neighborhoods, such as the religious and cultural traditions that have defined them, as well as layered aspirations about how revaluation may be shaped in the future. Much of this can be understood by exploring how residents manage financial assets in response to predictive governance technologies (speculative financial and other infrastructures, that manifest in housing appraisal, mortgage calculation, and crime prediction). The project trains a graduate researcher in qualitative methods of data collection and establishes research collaborations for future scientific capacity. The products of this research will be shared with community stakeholders, improving the public’s understanding of anthropological science and ethnographic scientific methods. This research examines the relationship between financial speculation, religious neighborhood organizations, and housing development. The project consists of twelve months of ethnographic and archival research including semi-structured interviews, audio-visual recording, and spatial analysis. The researcher asks how different anticipations for a neighborhood are formed and sustained by engagement with financial practices and infrastructures; how historical relationships interact with present day revaluation; and how new liquid assets are derived not only from housing, but also from public safety and design projects. The findings have intellectual merit for advancing anthropological theory related to the influence of religious tradition on socioeconomic behavior, particularly with respect to speculative technologies, as well as better understanding and confronting the convoluted processes of liquidity and assetization in contemporary markets. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-01

SUMMARY Despite the current prevalence of Alzheimer’s disease (AD), there are few effective disease-modifying therapies1. AD is characterized pathologically by amyloid-beta plaques (Aβ), neurofibrillary tau tangles, neuroinflammation, and neurodegeneration1. Microglia, the resident macrophages in the central nervous system (CNS), constantly patrol the CNS for damage2. In AD, microglia mount a strong pro-inflammatory immune response to Aβ4, which is partially effective at clearing Aβ in the early stages of AD but loses effectiveness as Aβ load increases4,5. Microglial deficiency in clearing Aβ is likely because microglia are not evolutionarily equipped with an optimal receptor to recognize and degrade Aβ3. A known microglial receptor recognizing Aβ is the triggering receptor expressed on myeloid cells 2 (TREM2), whose primary ligand is anionic phospholipids3,7 rather than Aβ. Aducanumab is an FDA approved anti-Aβ monoclonal antibody that has been shown to be effective at reducing Aβ plaques in AD.14,21. However, it also induces an excessive pro-inflammatory microglial phenotype that is associated with brain volume loss and amyloid-related imaging abnormalities in patients21-23. Chimeric antigen receptor (CAR) allows targeted recognition of specific antigens by immune cells and has been successfully used to target tumors8. Because of the lack of a specific anti-Aβ microglial receptor, CAR technology likely represents an important therapeutic strategy for AD. Traditional CAR therapy requires extensive resources as ex vivo engineering of immune cells is needed10. We propose to use blood brain barrier (BBB) crossing lipid nanoparticles (LNPs) to encapsulate mRNA encoding an anti-Aβ CAR and IL-10 to directly induce expression of anti-Aβ microglial CARs and IL-10 to promote an anti-inflammatory brain microenvironment in vivo. In Aim 1, we will develop two anti-Aβ CAR constructs that specifically detect Aβ via an aducanumab single chain variable fragment (scFv) and promote phagocytosis via the TREM2 or Fc receptor (FcR) signaling pathways. We will then package mRNA encoding the CARs and IL-10 in LNPs with anti-TREM2 antibody Fab on the LNP surface to promote preferential uptake by microglia, which upregulate TREM2 in the vicinity of plaques. We will transfect primary mouse microglia with these constructs or controls and measure phagocytosis of Aβ and microglial activation in vitro. We will proceed with the most effective construct for in vivo studies. In Aim 2, we will test whether the LNP-CAR can transfect microglia and reduce Aβ plaques in 5XFAD mice in vivo. We will administer LNP-CARs by intravenous injection into 5XFAD at several timepoints during amyloidosis. We predict LNP-CARs will effectively transfect microglia in vivo, will lead to increased microglial recognition and engulfment of Aβ plaques, and limit neuroinflammation, dystrophic neurites, neurodegeneration, and cognitive decline. In summary, we propose a strategy to treat AD by using cell-type specific LNPs containing mRNA encoding an anti-Aβ CAR construct and IL-10 to induce CAR microglia and an anti- inflammatory brain microenvironment in vivo.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY The baboon (Papio hamadryas) has emerged as a valuable primate model, offering profound insights into human health, behavior, and evolution. Despite their genetic and physiological resemblance to humans, the availability of baboon genetic resources, and the complex social dynamics within baboon colonies, population-based functional genomic studies in baboons and other non-human primates remain limited. To address this gap, we propose to capitalize on a unique and extensive resource—a large-scale collection of baboon tissue samples, amassed over a 13-year period at the Southwest National Primate Research Center (SNPRC). This collection encompasses 51 diverse tissue types, each sampled from at least 60 genetically characterized baboons. Such a comprehensive baboon tissue collection is unmatched in any other non-human primate species and offers an unparalleled opportunity for studying gene regulation across multiple tissues. The goal of this project is to conduct a large-scale, multi-tissue functional genomic study of gene regulation in baboons. Inspired by the Genotype-Tissue Expression (GTEx) Project in humans, our study aims to generate a comprehensive catalog of gene expression data derived from dozens of baboon tissues in a large sample of genotyped individuals. By leveraging bulk and single-cell RNA sequencing technologies, we will acquire transcriptomic data from 60 baboons across 51 tissues, encompassing vital organs such as the brain, heart, lung, liver, and adipose tissues, among others. Building upon the comprehensive baboon tissue collection and utilizing advanced genomic techniques, we will map expression quantitative trait loci (eQTLs) in baboon tissues. Drawing inspiration from the GTEx Project, we will determine the spatial distribution of eQTLs across genes and regulatory regions, explore patterns of eQTL sharing and tissue specificity, and disentangle the effects of cell type composition on gene expression by leveraging single-cell RNA-seq data. We will also investigate potential sex-specific effects on gene expression and cell type composition, enhancing our understanding of sexually dimorphic gene regulation in baboons. To maximize the impact and accessibility of our findings, we will develop the Baboon GTEx Portal—an open-access portal for baboon genomic data. Inspired by the successful human GTEx portal, this interactive website will provide unrestricted access to baboon data, eQTL information, and other research outcomes. To enable seamless comparisons with human GTEx data, the portal will incorporate a module for identifying orthologous genes and syntenic regions between baboons and humans, facilitating comprehensive comparative genomic studies in primates.

NSF Awards · FY 2025 · 2025-01

This award extends the current Broadening Participation in Computing Alliance, the LEAP Alliance, which addresses the critical broadening participation challenge of increasing the diversity of the future leadership in the Computing professoriate at research universities as a way to increase diversity across the field. The problem we address is stark and straight-forward: only 5.3% of the faculty (tenured, tenure track, teaching, research, instructors, and postdocs) at PhD-granting universities are from the following underrepresented communities: Black or African-American, Hispanic, American Indian/Alaska Native, or Native Hawaiian/Pacific Islander. Diversifying the computing professoriate is critically important to address because diverse faculty contributes to academia in several important ways. They serve as excellent role models for a diverse study body, bring diverse backgrounds to the student programs and policies developed by the department, and bring diverse perspectives to the research projects and programs as well as the courses that comprise the undergraduate and graduate curricular. Further, key national leadership roles, such as serving on national communities that impact the field of computing, often come from research universities. The extension builds upon the initial accomplishments and lessons learned of the BPC LEAP Alliance, which was launched in 2021 and consists of 30 unique institutions. The five-year extension entails two main activities: (1) the continuation and refinement of the LEAP Alliance strategies for increasing diversity in the computing professoriate and (2) the establishment of an Affiliates Program for strong cross-dissemination of good practices and lessons learned between the four cohorts and the affiliate member institutions. The plan is to start the Affiliates Program during year three of the extension. The shared purpose and broad vision of the LEAP Alliance entails three main approaches: (1) increase the diversity of PhD graduates from the Institutions that are the top producers of computing faculty; (2) increase the exposure of academic careers at the institutions that already have good diversity in their PhD graduates; and (3) increase the retention of undergraduate students from underrepresented communities at the institutions that send students to doctoral programs. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-01

The University of Chicago, University of Illinois, and Utah University seek to transform online computer science theory education by developing exercises delivered by online tools to provide better learning experiences for a broad set of students. Theory courses teach critical skills that help software engineers write efficient code, allowing them to optimize for saving energy, speed, reliability, etc. Undergraduate computer science instruction is utilizing an increasing amount of online learning in a variety of ways, including online homework activities only, online lectures with access to in-person office hours, and fully online courses. While introductory coding instruction has made great strides in developing exercise types amenable to online instruction, theory education lags behind. Algorithms and discrete math courses have long depended on hand-graded, large start-to-finish homework exercises, hindering the quality of its online instruction. If successfully developed and integrated into computer science instruction, such innovative solutions will increase student success in obtaining computer science degrees, especially students who are less confident in their abilities. This Computing in Undergraduate Education Transformation project will improve career outcomes for computing students and build a stronger computing workforce. This project will explore the design and use of online homework problem types for theory instruction integrating several attributes: instant, automated feedback, isolated skills, adaptive complexity, and culturally responsive contexts. First, the project team will explore isolated skill exercises, inspired by Parsons problems in coding and recent Proof Blocks in proof-building. These problem types will focus on individual skills rather than the entire problem-solving process. The purpose is to improve both student confidence and skills. Second, the project will explore adaptively scaffolded sequences, responding to student mistakes through gradually easier problems that scaffold their learning of an isolated skill. The purpose is to improve both student confidence and skills. After developing a robust set of base problems, a Large Language Model (LLM) will be used to produce equivalent variations of those base problems, all with different contexts. The purpose of these problems is to improve student engagement and skills. When analyzing challenges and strategies, TheoryABCs will address two focal populations: online students and students who are struggling academically in undergraduate algorithms courses. All activities will recruit from all students taking theory courses and will study how the interventions work on all populations. Through the three phases of the project—development, piloting, and evaluation—the project team will employ several techniques: during development, they will utilize think-alouds and focus group member checks; during pilot sessions, they will collect detailed automated data on student behavior, surveys on student reactions, and student submissions for student performance; and during evaluation, they will run a quasi-experimental comparison study between classrooms using the new exercise types and classrooms that do not. These strategies will improve career outcomes for computing students and build a stronger computing workforce. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Cellular adhesion is a process critical for animal development and is mediated by the adhesion family of G protein-coupled receptors (aGPCRs), an understudied group of cell-surface receptors that link cell adhesion to intracellular signaling. Cadherin EGF Laminin G seven-pass G-type receptors (CELSRs or ADGRCs) are conserved aGPCRs which are essential for animal development. CELSRs are involved in the process of planar cell polarity (PCP), where they are key for neural tube closure and the organization of several tissues including the nervous system. Mutations in CELSRs are strongly associated with developmental pathologies and Tourette syndrome. However, there is a lack of molecular-level insight into CELSR function, and this hinders understanding of CELSR-mediated pathophysiology and future therapeutic development. CELSRs have large extracellular regions (ECRs) containing 23 domains which mediate cell adhesion and modulate intracellular signaling. In addition, CELSRs have large intracellular regions (ICRs) that mediate intracellular events, yet the ICR interactome is undefined. As preliminary data for this proposal, I determined the 4.3 Å cryo-EM reconstruction of the mCELSR1 ECR with 14 domains resolved in a compact conformation. I have also optimized assays to examine CELSR-mediated adhesion and signaling in cells. Finally, I have conducted bioinformatic analysis which identifies protein-protein interaction motifs in the ICR and begun cloning CELSR-APEX constructs to conduct a proximity labeling screen. My central hypotheses are that the compact CELSR ECR conformation regulates cell adhesion and signaling, and that the CELSR ICR mediates non-canonical events. This proposal aims to determine the structural basis for regulation of CELSR function by its ECR, and to identify non- canonical binding partners of the ICR. I propose three specific aims: First, I will improve my cryo-EM reconstruction of the mCELSR1 ECR in order to build an experimentally derived atomic model, with help from cryo-EM expert Dr. Minglei Zhao. Second, I will test disease associated variants for their ability to alter the functions of CELSR1. This aim will grow my experience in cell-based assays. Third, I will discover binders of the CELSR1 ICR using a proximity labeling screen, and in parallel, pursue likely targets such as RhoGEFs. I will be trained by my co-mentor and GPCR-APEX expert Dr. Andrew Kruse, and I will learn to interrogate the results of the screens from GPCR signaling expert Dr. Silvio Gutkind. This proposal will result in a mechanistic description of ECR-dependent regulation of CELSR function, explaining how dysregulation of this protein can contribute to disease. I will also identify the CELSR ICR interactome; this will give me the material to study the structural biology of non-canonical signaling downstream of aGPCRs. In the Araç laboratory, I will be provided the opportunity to work with the world leader in aGPCR structural biology; I will continue to develop my skills as a scientist in the world-class environment that the University of Chicago provides, and with my mentoring team I will develop the material and skillsets to start my own independent laboratory at a research-intensive institution.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Hypothyroidism is a metabolic disorder that affects nearly 10% of the US population and directly contributes to over $400 million in healthcare costs annually. The primary treatment is to replace low thyroid hormone levels with levothyroxine (LT4) and normalize serum thyroid stimulating hormone (TSH). The TSH level provides clinicians with a measure of disease control over the last 2 months. If the TSH level is above or below the normal range, the clinician may adjust the LT4 dose and retest TSH. However, observational evidence suggests that the test-and-adjust treatment approach is inadequate for many patients, as one-quarter to one- half of patients experience uncontrolled TSH levels. Uncontrolled TSH levels cause systemic symptoms and increase the risk of adverse cardiovascular (CV) outcomes. However, our understanding of the impact of uncontrolled TSH levels on health outcomes is based on cross-sectional data and does not account for the cumulative exposure of uncontrolled TSH levels over time. In Aim 1 of this proposal, using real-world clinical data, the PI (Dr. Matthew Ettleson) will determine the association between cumulative TSH control and CV outcomes in patients with LT4-treated hypothyroidism using longitudinal analysis methods. Given the high frequency of uncontrolled TSH levels, strategies are also needed to improve the long-term management of hypothyroidism. In other chronic diseases, machine learning (ML) approaches and clinical decision support have been leveraged to individualize treatment and improve outcomes. In Aim 2, the PI will develop an ML model to identify which patients are at high risk of uncontrolled TSH levels within the next year of LT4 treatment. In Aim 3, the PI will seek to improve clinical practice by designing and implementing a clinical decision support system that identifies high risk patients, informs clinicians of monitoring gaps, and provides best practice recommendations at the point of care. The results of these studies will be used to inform an R01 proposal that will examine the effectiveness of risk-based monitoring approaches and clinical decision support to improve TSH control in LT4-treated patients. The purpose of this career development award is to support the PI in his long-term career goal of becoming a nationally recognized, independent health services and outcomes researcher with expertise in improving thyroid disease management. To meet his research and career goals, the PI will acquire skills in the following training areas that complement the research aims: 1) longitudinal analysis, 2) predictive modeling, 3) clinical informatics and implementation science, and 4) complete the Master of Science in Public Health Sciences for Clinical Professionals degree. The PI will work closely with his mentorship team, led by Dr. Neda Laiteerapong and Dr. Antonio Bianco, to meet the proposed research and training goals. The project will take place at the University of Chicago, a world-renowned institution with high-impact research programs in thyroid disease and health services and outcomes research.

NIH Research Projects · FY 2026 · 2025-01

Project Summary / Abstract Working memory is the ability to hold and manipulate information in short-term memory in the absence of sensory input. Recent investigation into the neural underpinnings of this key cognitive ability has highlighted the existence of distributed working-memory representations across the cortex of macaques and humans. However, we still do not understand how microcircuit components in different cortical areas support their potentially distinct contributions to working memory. To answer this question, my laboratory has developed a new working-memory paradigm for mice navigating in virtual reality, in which short-term memory is temporally disentangled from other task computations, and its duration manipulated systematically. This will allow for the integration of the unique genetic and optical toolkits available for mice. Our preliminary data from mesoscale calcium imaging of animals performing this new task show that the mouse dorsal cortex also contains distributed working-memory representations. Further, these distributed representations map onto a gradient of spontaneous activity timescales that increase from sensory to frontal areas. This is such that the primary visual cortex (V1) is active exclusively during short memory delays, whereas frontal areas such as the premotor cortex (M2) are preferentially recruited when sensory information needs to be remembered over seconds. Here, we will ask how genetically identified cell types in V1 and M2 distinctly interact to generate different activity timescales and patterns of recruitment during working memory. In particular, we will test the hypothesis that differences in the amount of recurrent excitation and the ratio between inhibition mediated by somatostatin- and parvalbumin- positive interneurons explain activity patterns during both spontaneous and working-memory behaviors. To accomplish this, we will use simultaneous two-photon Ca2+ imaging and optogenetic stimulation of single neurons to compare how V1 and M2 differentially respond to focal excitatory input as mice behave spontaneously. Moreover, we will silence different subtypes of inhibitory interneurons in each area to understand their role in modulating excitatory activity timescales in vivo, measured with two-photon microscopy or electrophysiology. Finally, to understand how excitatory neurons interact with different inhibitory-neuron subtypes to result in distinct patterns of task engagement of V1 and M2, we will simultaneously image from pairs of neuronal types using two- photon microscopy as mice perform our new working-memory paradigm. Thus, we will use an innovative set of approaches to understand how distinct microcircuit arrangements across the cortex support distributed working- memory representations. Beyond its relevance for basic neuroscience, our work will have translational implications: alterations in both cortical intrinsic timescale hierarchies and working memory have been reported in normal aging, autism, and schizophrenia.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are devastating neurodegenerative diseases with no cure to date. The most common genetic cause of ALS/FTD is a hexanucleotide GGGGCC (G4C2) repeat expansion mutation in the C9ORF72 gene. The repeat is transcribed in both directions, producing sense G4C2 and antisense CCCCGG (C4G2) transcripts that are translated into six dipeptide repeat (DPR) proteins. The GGGGCC mutation is thought to cause ALS via three non-mutually exclusive mechanisms: a loss- of-function mechanism due to reduced expression of C9ORF72 protein, and gain-of-function mechanisms due to toxic repeat-containing RNA and/or DPRs. Sense and antisense RNA and DPRs accumulate in the central nervous system of C9ORF72 ALS/FTD patients and have been shown to be toxic in multiple model systems. To date, most studies have focused on the transcription and translation of the sense GGGGCC transcript. Hence, we know very little about how the antisense CCCCGG RNA is transcribed and translated. Importantly, recent clinical trials only targeting sense GGGGCC transcripts failed, suggesting that antisense CCCCGG RNAs and their DPRs should be explored as therapeutic targets. In Aim 1 of this proposal, the yet-unknown transcription start site (TSS) of the antisense transcript will be located using 5’ Rapid Amplification of cDNA Ends (RACE). Upon locating putative TSSs, the site(s) will be functionally validated via CRISPR/Cas9 mutagenesis in C9ORF72 patient-derived induced pluripotent stem cells (iPSCs). Then, I will target the TSS via CRISPR interference (CRISPRi) - a catalytically inactive Cas9 enzyme will interfere with transcription of the antisense strand, and the effects of blocking antisense strand transcription will be assessed in vitro using iPSC-derived motor neurons. In Aim 2, antisense oligonucleotides (ASOs) will be used to selectively degrade antisense repeat RNA. First, the candidate ASOs will be assessed for their ability to decrease DPR and transcript expression and reduce cell death in vitro using iPSC-derived motor neurons. Next, candidate ASOs will be administered to mice expressing 35 copies of the antisense CCCCGG repeat to determine whether they can rescue ALS/FTD pathology and symptoms. Altogether, successful completion of this proposal will elucidate a new target (antisense CCCCGG repeat RNA) of therapeutic interest for ALS/FTD. Such knowledge may be relevant for multiple other neurodegenerative diseases which are caused by bidirectionally-transcribed repeat expansions, including Huntington’s disease, spinocerebellar ataxias, and Friedreich ataxia.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Most transcription occurring in the human genome produces RNAs that do not encode proteins, and disruption of these non-coding RNAs (ncRNAs) is associated with multiple cancers. It is necessary to fully understand the role ncRNAs play in disease so that treatments and medicines can be developed. This project studies a particular ncRNA called HOTTIP which controls the expression of HOXA genes during the development of limbs. HOTTIP recruits the histone methyltransferase MLL1 to HOXA genes, however the mechanism of recruitment is unclear. By understanding how HOTTIP functions as a regulatory molecule, we can improve our knowledge of ncRNAs generally and identify ways to target ncRNAs therapeutically. This project involves creating a new technology through molecular engineering to determine the role of HOTTIP rapidly and confidently in human cells. It will be possible to uncover the exact way HOTTIP interacts with the MLL1 complex, and the degree the RNA molecule of HOTTIP itself is central to regulation of HOXA genes. This technology can then be used to study the thousands of other ncRNAs found in the human genome.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Human development intricately relies on precise fate determination during gastrulation, a pivotal stage where a uniform epithelium undergoes dynamic rearrangement to form the diverse tissues of the body plan. Classical embryology has identified pathways and gene expression patterns guiding predictable tissue formation, yet emerging hypotheses reveal a deeper complexity in cellular behavior and fate determination. When a cell dynamically alters its physiology to migrate in response to nearby signals, its microenvironment undergoes continuous changes as it moves. How does the cell interpret these dynamic shifts to regulate its downstream functions effectively? This proposal delves into the dynamics of early mammalian development, focusing on mesoderm cell behavior during gastrulation and its implications for tissue formation and cell fate. I aim to challenge the conventional notion of embryonic development as a linear series of phases by dissecting the interplay between cell movement and the changing milieu, highlighting the dynamic and non-linear nature of tissue formation. Exploiting an in vitro gastruloid model, I will explain the mechanisms underlying mesoderm migration, offering a unique opportunity to dissect migration dynamics and their impact on tissue organization. My preliminary data suggests that mesoderm cells exhibit high motility and contribute significantly to downstream tissue organization, highlighting the potential of altering migration kinetics to influence mesoderm architecture. Through a combination of genetic perturbations, functional analysis, and computer vision, this proposal aims to establish a novel approach to understand the regulatory pathways governing mesoderm migration and its role in tissue architecture. How does the physical environment dynamically influence mesoderm fate? To address this question, my project is twofold: firstly, unraveling the mechanisms regulating mesoderm cell migration during fate patterning; and secondly, understanding how migration dynamics shape tissue form and influences cell fate decisions. Overall, this study aims to uncover fundamental insights into the complexity of mesoderm cell behavior during embryonic development. These findings contribute to our broader goal of understanding and eventually controlling cell behavior.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Mechanical Information Processing from Sub-cellular to Tissue Scales The mechanical behaviors of cells control diverse physiological processes including cell proliferation, migration, fate and apoptosis; these behaviors are also key contributors to pathologies such as cancer and cardiovascular diseases. Within multicellular tissues, cell mechanics are largely determined by feedback mechanisms, which coordinately regulate the actin cytoskeleton, cell-matrix adhesions, and cell-cell adhesions. It has become evident that cytoskeletal assemblies are complex mechanochemical systems that employ force-sensitive biochemical regulation to maintain and modulate mechanical response. While the basic architectures of these systems have been suggested, approaches are needed to understand their force-sensing and responses. This will elucidate the mechanical design principles of the cytoskeleton, enabling novel methods for the engineering of a cell or tissue’s shape and dynamics. To address this challenge, my research program leverages an innovative combination of analytical methods: cell biophysics, molecular cell biology, live cell imaging, mathematical modeling, and optogenetics, allowing us to investigate the machines and materials constructed within the cytoskeleton of adherent cells. Our goals over the next five years are to expand the understanding of adherent cell mechanics and mechanobiology. We will explore the underpins of the force-sensitive remodeling of cell-cell adhesions and the role it plays in contact inhibition of proliferation. We will also investigate mechanisms of mechanosensing via LIM domain proteins, a new class of force-sensors within the actin cytoskeleton. We will develop new experimental approaches with which to probe the mechanochemical circuitry within cells, including establishing a new field of data-driven biophysics modeling. Thus, our work will broadly impact the field of cellular biophysics and mechanobiology.

NIH Research Projects · FY 2026 · 2024-12

Project Summary: The continued presence of chemical weapons poses a significant threat to public health and safety. Exposure to skin blister agents, which are most commonly used in chemical warfare, can cause severe skin inflammation and tissue destruction, leading to permanent disfigurement and disability. However, the mechanism of vesicant-induced skin blistering is complex and poorly defined, which hinders the development of effective medical countermeasures. Dynamic remodeling of cell adhesions is essential for many biological processes, such as cell movement, developmental morphogenesis, and tumor metastasis. Disruption of cell adhesion is a critical step during skin chemical injury. Cell adhesions are closely associated with the underlying cytoskeletal networks, which together provide the structural framework for the cells. Turnover of cell adhesion requires coordinated activities of cytoskeleton. Previous work from our group demonstrates that spectraplakin family protein, Actin Crosslinking Factor 7 (ACF7) promotes cell adhesion turnover by targeting microtubule plus ends toward cell adhesions. ACF7 harbors both microtubule and F-actin binding affinity, and the latter is regulated by focal adhesion kinase (FAK). Our recent study shows that tyrosine phosphorylation of ACF7 by FAK plays an indispensable role in coordinated cytoskeletal dynamics and cell adhesion turnover in skin keratinocytes. Interestingly, with ACF7 skin conditional knockout (cKO) model, we found that loss of ACF7 can attenuate skin damage induced by Phenylarsine oxide (PAO), a lewisite analog. With primary mouse keratinocytes, we found that PAO can induce FAK activity and enhance ACF7 phosphorylation, which lead to increased cell adhesion turnover in vitro. Together, our previous research and preliminary results raise the intriguing hypothesis that skin vesicants can regulate cell adhesion turnover through a novel signaling network centering on ACF7. In this proposal, we will employ an integrative approach to explore the basic molecular mechanism underlying skin vesication. We will determine the role of ACF7 and FAK in PAO or NM (nitrogen mustard)-induced skin blistering in vivo with mouse cKO models. We will use quantitative and live cell imaging approach to investigate how skin vesicants regulate cell adhesion and cytoskeletal dynamics through ACF7 and FAK signaling in vitro. Hemidesmosomes play a critical role in maintaining skin tissue integrity and mechanical stability. In this proposal, we will use a unique mouse skin organoid culture and engraftment model to investigate hemidesmosome dynamics and its regulation by ACF7 in response to skin vesicants. Together, by leveraging our extensive expertise in cell adhesion and cytoskeletal dynamics, the proposed study will fulfill a significant gap in our understanding of skin chemical injuries and reveal potential therapeutic targets for treatment.

NSF Awards · FY 2024 · 2024-12

Two major goals of probability theory are to address the question of how large complex systems work and to identify the geometry of their evolution. Probabilistic models are widespread in fields like biology, statistical physics, quantum mechanics, and machine learning. Examples include models of cancer growth, spread of disease in population, governing principles of subatomic particles, black holes, neural networks, etc. The purpose of this project is to understand the geometry and intrinsic properties of a string of models that are representatives of these examples. The project aims to resolve open questions in those fields based on tools that the investigator has developed. Domino tilings, random matrices, and stochastic six vertex models are areas of intense interest in the field of statistical physics, while Liouville conformal field theory (LCFT) and theory of optimal transport have gained immense attention in the fields of quantum mechanics and machine learning. This project revolves around questions in those areas and aims to acquire new insights about their geometry and integrability. In particular, this project plans to: (1) find laws of iterated logarithms and fractal dimension of models in the Kardar-Parisi-Zhang (KPZ) universality class including the KPZ fixed point, edge spectrum of random matrices, and domino tilings; (2) build a unified framework for studying the moment formulas of interacting particle systems and vertex models including the stochastic six vertex model; (3) rigorously prove modular transformation properties of conformal blocks of LCFT and partition functions from gauge theory; and (4) study the convergence of entropically regularized optimal transport to optimal transport when the regularization vanishes. By intermingling ideas from various fields including geometry of polymers, representation theory, Riemann-Hilbert techniques, quantum groups, and convex geometry, the investigator aims to resolve questions that were hard to tackle with other methods. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-12

African Americans (AA) have among the highest colorectal cancer (CRC) incidence and mortality in the US. Environmental factors influenced by social factors, especially high fat diets, are known to increase CRC risk, but how these factors contribute to CRC risk differences is largely unknown. Bile acids (BA), produced in response to dietary fat, are converted by the gut microbiome to secondary BA, especially deoxycholic acid (DCA) and lithocholic acid (LCA), that can be carcinogenic in the human colon. Previous studies suggested differences in BA concentration and metabolism between AA and non-Hispanic Whites (NHW), but these preliminary findings require rigorous validation and further investigation. Colonic responses to BA could also differ between populations and modulate CRC risk. We developed an innovative experimental framework using colonic organoids to study host-environment interactions in colonic tumorigenesis that has been successfully applied to identify cancer-related, inter-ethnic responses to relevant environmental factors. In this proposal, we will study 3 aspects of BA metabolism to determine if there is a connection to CRC risk and observed differences in CRC between heterogenous groups. As an R21 proposal, the goal is to test the hypothesis of population differences in one or more of these factors that, if found, would then be studied through mechanistically-focused investigations in the future. Specifically, we will: 1) Compare serum BA composition in self-identified AAs and NHWs leveraging a prospective study called COMPASS, 2) perform microbiome profiling in tissue and stool from AAs and NHWs with specific attention to pathways involved in BA conversion, and 3) test for differences in transcriptional and cellular responses to DCA and/or LCA in colonic organoids from individuals of African and European descent. Importantly, we will control for relevant covariates such as age, sex, diet and social factors. If one or more of these hypotheses is confirmed, our results will provide critical preliminary data to support a future proposal to dissect underlying mechanisms of observed differences in BA metabolism and colonic responses between populations and how these could impact CRC risk. This study has potential for high impact to elucidate the interrelated roles of diet, BA metabolism and colonic responses in CRC that could translate into future “precision prevention” trials and new biomarkers of CRC risk especially in AAs who experience unequal burden of disease.

NIH Research Projects · FY 2026 · 2024-12

Project Summary The proposed research sets out to examine the role of BNIP3 and mitophagy in muscle atrophy during cancer cachexia that is prevalent in pancreatic ductal adenocarcinoma (PDAC). Using physiologically relevant genetically engineered mouse (GEM) models of PDAC, we examine how BNIP3 promotes atrophy of myofibers with a focus on its role in reducing mitochondrial mass to levels incompatible with sustained growth and homeostasis of specific myofiber types. We also examine how reconstitution of myofibers with different mutant forms of BNIP3 affects key signaling pathways and myofiber growth. We also address the stresses and signals that may explain induction of BNIP3 in muscle by growing PDAC tumor and if these explain the differential muscle atrophy seen between males and females. These mechanistic insights are then interrogated in human PDAC patient muscle samples to determine whether BNIP3 levels in patient muscle predicts the extent of cachexia and survival outcomes (Aim 1). Separately we address how muscle atrophy promotes pancreatic tumor growth and progression by examining how muscle atrophy increases the release of proteins and metabolites into the bloodstream at early stages of pancreatic cancer that may promote progression of benign PanIN lesions to PDAC and increased tumor growth. Finally, we examine whether such muscle-derived factors in the circulation could serve as reliable biomarkers of early-stage pancreatic cancer that will be important for earlier clinical intervention and longer-term survival outcomes for PDAC patients (Aim 2).

NSF Awards · FY 2024 · 2024-12

The distribution of matter throughout the cosmos carries information about the origin, future, and composition of the Universe. However, obtaining high-precision measurements of the matter distribution is challenging: most of the matter is in the form of invisible dark matter, making it impossible to observe directly. Instead, techniques such as gravitational lensing – the bending of light by gravity – must be used to infer where the matter is. With this research program, scientists at the University of Hawaii and the University of Chicago will analyze four different and highly complementary probes of the matter distribution from state-of-the-art astronomical surveys to obtain precise and unbiased constraints on the properties of the Universe. The team will use measurements of galaxy positions and gravitational lensing of galaxies from the Dark Energy Survey (DES), measurements of gravitational lensing of light from the cosmic microwave background (CMB) by the South Pole Telescope (SPT) and the Atacama Cosmology Telescope (ACT), and finally, measurements from SPT and ACT of the scattering of CMB light with electrons. By analyzing these complementary probes in concert, the team will reduce uncertainties on the properties of the Universe, minimize potential biases in their constraints, and obtain a more complete picture of the matter distribution. This award will additionally support development of new teaching modules designed to give high school and undergraduate students the opportunity to learn from real data and gain hands-on experience in data science. Statistics of the matter distribution are predicted by the cosmological constant and cold dark matter (LCDM) model, and comparing these predictions to observations is a key goal of current and future cosmic surveys. Recently, measurements of the late-time matter distribution from galaxy surveys have shown hints of disagreement with extrapolations of early-Universe measurements that assume LCDM. This disagreement could result from fundamental problems with LCDM, or from systematic uncertainties impacting the measurements. Using new data from DES, SPT, and ACT, the team will measure and analyze cross-correlations between CMB lensing, galaxy positions, galaxy lensing, and the thermal Sunyaev Zel'dovich effect in order to perform a definitive assessment of tension with LCDM, test alternative cosmological models, and enable improved constraints with future surveys. The broader impacts of the proposal will be to provide training in data science to high school, undergraduate and graduate students, and to increase public engagement with astronomical surveys. The PIs will develop a set of new teaching tools based on Python notebooks that give high school and undergraduate students the opportunity to learn from real data. These teaching tools will be implemented in classrooms in Honolulu and Chicago. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-12

The role of 'polymorphic microbes' in cancer development and progression has been extensively studied, but research on the role of fungi (mycobiomes) is surprisingly limited. To address this gap, we have developed an innovative 3D-organotypic lung (iLung) model derived from human pluripotent stem cells (hPSCs). This model in combination with live spore-based exposure/infection methods, allows for the study of direct contact between epithelial cells and pathogens in the culture media, providing more accurate representation of real-life exposure, infection, and intratumoral colonization. Using this model, the team has demonstrated extensive DNA damage and identified specific DNA breakage motifs and mutational signatures in lung cells infected with spores of Aspergillus fumigatus (Asp), a common fungal pathogen found in human airways and lung cancer samples. Notably, significant mutations were observed in important cancer genes, and lung cancer lines treated with Asp showed more advanced and aggressive tumor phenotypes. The team also noticed increased levels of IL-33 and other type 2 cytokines, IL-4, IL-5 and IL-13, known regulators of Th2-type immune responses, in treated cells. These preliminary studies led to the hypothesis that mycobiomes can promote malignancy either directly, by inducing mutations, or indirectly, by reshaping host immune responses. The team proposes to test this hypothesis using the hPSC-derived iLung system, live spore- based infection models, and advanced technologies such as identification of mutational signature, single-cell transcriptomics, and molecular modeling using quantum mechanics calculation. The research project is centered on three aims. The first aim is to establish the carcinogenic effect of fungi on lung cancer, particularly focusing on Asp and other common fungal species (e.g. Alternaria) in lung cancer. The second aim is to understand the mechanism of fungal mutagenesis, examining both direct and indirect routes, such as the role of mycotoxins and the increase of reactive oxygen species (ROS). The third aim is to determine the effect of fungus-induced remodeling of host immunity in lung cancer. The research's expected outcome is to illuminate the mechanisms by which fungi contribute to cancer development and progression. This could pave the way for the development of novel diagnostic, preventive, and therapeutic strategies against cancer influenced by mycobiomes.