Northwestern University

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Human Immunodeficiency Virus 1 (HIV-1) infection outcome is variable between single host cells, even within clonal populations. Host factors are variably expressed and can promote susceptibility to infection and latency, a state wherein a copy of the virus remains in the host genome, posing a serious therapeutic challenge. Yet, no lasting solutions to these problems exist to date because we lack a comprehensive knowledge of the drivers of host cell state to distinct infection fates. Targeting the source of single cell variability in HIV-1 infection may provide strategies for its prevention, treatment, and cure. My proposed work will investigate how certain cell states permit HIV-1 infection and latency—two major roadblocks to lasting cures. Here, I propose to 1) nominate host cell state drivers of HIV-1 susceptibility, and 2) redefine HIV-1 infection at the single-cell level using a new viral isoform capture method. Toward this end, I will develop preVIEU, a multimodal framework combining DNA barcoding, single-cell profiling, viral mRNA isoform capture, and computation. To determine the extent HIV-1 infection fate is predestined by cell state, I will barcode primary CD4+ T cells and track if “twin” sibling cells share the same fate upon HIV-1 challenge. To then reveal what specific state predetermines a cell to either active or latent infection, I will profile cells using CITE-seq—combined single cell transcriptomic and protein abundance measurement—and link one sibling’s initial state before viral exposure to the other sibling’s infection fate via their shared barcode. I will experimentally validate that these states drive a specific fate, and screen for proteins and pathways underpinning these states to identify factors controlling infection outcomes. To better understand infection dynamics within single cells, I will develop the viral isoform capture component of preVIEU that I will then apply to study cell-, cell type-, and tissue-specific infection states in SIV-infected, ART-suppressed macaque samples. Lastly, I will monitor latency reversal in single cells to determine synergistic drug treatments to improve the targeting of the latent reservoir. Overall, I will develop generalizable frameworks to infer host cell infection state-to-fate mappings at unprecedented resolution to further our understanding of HIV-1 infection dynamics and pave the way for precise disease control strategies.

NSF Awards · FY 2025 · 2025-09

Loss of minerals from teeth owing to tooth decay or erosive tooth wear, or from bones owing to osteoporosis, compromises mechanical function, causes pain, and affects quality of life. Demineralization involves the dissolution of biological apatite crystallites. This project will create a computational model that will accurately predict time-dependent changes in mineralized tissue structure and composition. Based on robust structural, compositional, and thermodynamic data or quantum chemical computation, this model will show how the phases, interfaces, and dissolution dynamics contribute to healthy and pathological mineralized tissues. In the long-term, this model will be able to identify risk factors for enamel dissolution and enable personalized minimally invasive interventions to address mineral loss in teeth. The project will provide early career researchers with the skills to apply state-of-the-art computational and experimental materials science approaches to research in life sciences and engineering. Demineralization of teeth and bones is linked to multiple debilitating disorders with poor quality of life. These disorders involve the dissolution of apatite crystallites, and in dental enamel an amorphous intergranular phase (AIGP) is also involved. Minor constituents modulate the solubility and orientation-dependent interfacial free energies during demineralization. The interplay between the microstructure and composition of bulk phases, interfaces, mechanical stresses, and dissolution dynamics remains poorly understood, limiting predictive modeling. This is a major bottleneck to design clinically-relevant minimally invasive interventions. Therefore, this project will create and validate a modular and expandable phase field model (PFM) based on robust structural, compositional, and thermodynamic data. The team will use high-fidelity density functional theory (DFT) to model apatite structure and solubility, and determine orientation-dependent interfacial free energies in the physiological environment. A reverse Monte Carlo (RMC) approach constrained by experimental data will be used to model the composition-dependent structure, and DFT will predict properties of the AIGP. The project will expand the capabilities of PFM to account for multiple phases with composition-dependent solubility, diffuse transport and speciation in narrow pores, and the orientation-dependent surface energy and interface mobility. The project will refine and rigorously validate the PFM by comparing predicted dissolution rates of synthetic apatite and murine enamel to experimental data, and perform a sensitivity analysis to identify factors that contribute to rapid enamel dissolution to improve the accuracy of the model. 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 2025 · 2025-09

PROJECT SUMMARY. While neuromuscular plasticity is the basis of the field of physical medicine and rehabilitation, how the most functionally meaningful muscle architecture parameters adapt has not been rigorously studied in humans. Commonly, orthopaedic surgery implements significant geometric re-designs to the musculoskeletal system. Frequently, these re-designs are substantial enough that, theoretically, they should induce long-term adaptation in optimal fascicle length. Thus, studying muscle response to orthopaedic intervention provides novel opportunities to advance our understanding of these adaptations and their resultant functional effects. We have chosen to study orthopaedic surgical repair of the Type II SLAP lesion of the long head of the biceps tendon because, due to the current standard of care, it presents a unique model system to evaluate skeletal muscle structural adaptation in vivo. Type II lesions are typically repaired in one of three manners: SLAP repair, biceps tenotomy, or biceps tenodesis. Importantly, because each surgical approach addresses reattachment of the tendon uniquely, different muscle-tendon structures are imposed. In SLAP repair, the superior labrum and biceps tendon are reattached to the glenoid, attempting to restore the muscle-tendon unit to approximately pre-tear length and, presumably, tension. In tenotomy, the tendon is detached completely (sparing its full length) and allowed to retract into the bicipital groove where it frequently adheres. In tenodesis, the tendon is resected and reattached to the proximal humerus. The overall objective for this pilot study is to identify if the different origin-to-insertion distances imposed by three surgical approaches to Type II SLAP lesion repair lead to chronic differences in fascicle length substantial enough to yield measurable effects on isometric and isokinetic elbow supination strength. In Aim 1a, we will utilize extended field-of-view ultrasound to measure fascicle length. This retrospective study will quantify muscle architecture of the biceps brachii, in vivo, in both arms of individuals who have undergone unilateral Type II lesion repair from each of the three primary surgical groups and in a control, nonsurgical group. In Aim 1b, we will characterize biceps tendon geometry following repair and a non-surgical population, providing foundational knowledge which will be useful to surgeons in determining feasible repair strategies. For completeness, we will also quantify muscle volume. In Aim 2, we will determine if these changes in muscle-tendon structure map to measurable effects in muscle strength. We will quantify active muscle function in both arms of the same participants using isometric and isokinetic dynamometry. Upon successful completion of the proposed research, we expect to provide novel in vivo data in humans, characterizing fiber adaptation among three orthopaedic surgical techniques, including corresponding measures of active muscle function. This contribution is expected to be immediately significant for orthopaedic surgeons who treat Type II SLAP lesions. More broadly, these data will improve our understanding of adaptation in the neuromuscular system, which is critical to the design of effective clinical interventions.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The evolution of cadherins enabled terrestrial metazoans to develop complex tissue barriers, with desmosomal cadherins anchoring elastic and tough intermediate filaments (IF) to the plasma membrane at cell-cell junctions, thus providing mechanical strength to tissues and organs. Uniquely expressed in stratified epithelial keratinocytes, the desmosomal cadherin, Desmoglein 1 (Dsg1), also has more recently appreciated functions in driving the process of stratification through cell delamination and suppressing inflammatory signaling. Surprisingly, these Dsg1-dependent functions may be mediated by shared molecular machinery comprising Arp2/3-associated actin remodeling proteins. Previous studies from my lab demonstrated that Dsg1 recruits an Arp2/3 complex to promote actin polymerization at desmosomes, facilitating keratinocyte migration to the next superficial layer by altering cell mechanics in the stratifying cell. However, the mechanism by which Dsg1 maintains Arp2/3 at the plasma membrane remains unclear. My data points to a role for Nck1, an adaptor protein known to facilitate Arp2/3 activation via N-WASP, which was identified as a potential desmosome interactor in a publicly available proteomic screen. Our data suggest that Dsg1 recruits Nck1 to desmosomes through Dsg1 Y1042, enabling interactions with N-WASP and Arp2/3 at the plasma membrane. Silencing Nck1 or introducing a Y1042F mutation in Dsg1 impairs epidermal stratification, suggesting that Dsg1 regulates actin remodeling via N-WASP through tyrosine phosphorylation at the Nck1 binding site. Notably, the Nck1 associated protein, N-WASP is also present in the nucleus, where it can suppress the expression of inflammatory cytokines, including IL-23, known to cause inflammation in Dsg1-deficient patients and in the common inflammatory disorder psoriasis. These data lead to my hypothesis that through Nck1, Dsg1 recruits N-WASP/Arp2/3 complex in a non-receptor tyrosine-kinase (NRTK) dependent fashion to control stratification and, through downstream signaling, directs N-WASP to the nucleus to help manage inflammation. In Aim 1 I will determine how Dsg1 recruits the N-WASP-actin complex to the membrane to drive actin remodeling for cell delamination using assays to assess protein-protein interactions, actin polymerization, and keratinocyte stratification. In Aim 2 I will elucidate how Dsg1 governs N-WASP localization and stability through serine/threonine kinase signaling to modulate inflammatory pathways using live cell imaging, cell fractionation and analysis of keratinocyte cytokine expression. These studies promise to reveal how Dsg1 integrates its roles in creating the physical and immune barriers through shared mechanisms and may reveal new therapeutic avenues for strengthening and repairing the epidermal barrier.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY: Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic stem cells (HSPCs) where normal 3D genome architectures are essential for proper lineage-specific functions. Repressive epigenetic features, such as Histone 3 Lysine 9 trimethylation (H3K9me3), play vital roles in maintaining healthy HSPCs, but we still understand very little about their roles in promoting AML. Marking constitutive heterochromatin, H3K9me3 is deposited by methyltransferases and participates in heterochromatin condensation; however, its significance in myeloid 3D genome architecture remains unclear. I identified SUV39H1, a key H3K9-specific methyltransferase, as a major depositor in AML cells, essential for sustaining proliferation and myeloid differentiation gene signatures. Moreover, in AML cells treated with DNA hypomethylating agents (HMAs), alterations in H3K9me3 distribution are observed. This suggests a potential role of SUV39H1, the major H3K9me3 depositor, in heterochromatin reorganization in the context of DNA hypomethylation. Together, I hypothesize that SUV39H1-mediated H3K9me3 shapes AML-associated nuclear architecture, and that the interplay between SUV39H1-driven H3K9me3 and DNA methylation status regulate heterochromatin integrity. To test this, I will profile leukemic transcriptomic programming and assay the high-order genome organization in SUV39H1-depleted AML cells to define the genomic mechanism in how SUV39H1 protect AML cells from differentiation in Aim 1. I will determine if SUV39H1 is necessary for AML cells to survive DNA hypomethylation by re-distributing H3K9me3 in Aim 2. This proposal seeks to investigate SUV39H1's role in preserving 3D genome architecture in AML cells and identify it as a potential therapeutic target to augment FDA-approved HMA therapy. If successful, this study will yield crucial insights into the determinants of 3D chromatin organization in AML. My ultimate career goal is to lead my own research team in genome and leukemia biology, driven by my personal experience as a leukemia patient. The successful completion of my proposed work hinges on mastering experimental methodologies and gaining in-depth knowledge in genomics and epigenetics. This expertise will empower me to achieve my goals. Dr. Feng Yue’s laboratory, with its extensive expertise in both leukemia biology and genome biology, is crucial for my training. By following the training plan outlined in this proposal, I will receive comprehensive training in various techniques, acquire essential knowledge, benefit from mentoring, and enhance my presentation skills. Conducting my research under the guidance and support of Dr. Yue ensures that I am on the right path to achieve my goals.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Recent breakthroughs in machine learning have stunned the world by making it possible to accurately predict folded structures for an enormous variety of protein sequences. These breakthroughs signaled the power of innovative algorithms and large datasets to unlock the hidden information in a protein’s sequence. Still, this only scratches the surface of what protein sequences can tell us. The goal of this project is to uncover the next layer of information hidden in protein sequences by measuring global folding stability and folding energy landscapes for thousands to millions of protein domains. Due to experimental limitations, these properties have historically been challenging to investigate at scale. Using new experimental methods developed by our lab, this project will lead to unique, massive datasets quantifying these two properties. These datasets will empower computational researchers in our own lab and around the world to develop new predictive models that can be applied in drug and vaccine development as well as in basic research. Global folding stability describes the physical propensity of a protein sequence to fold or unfold, and stability influences nearly every other protein property, including function, aggregation propensity, cellular abundance, immunogenicity, and more. Engineering higher stability proteins is a major goal in drug and vaccine development, and determining how genetic variants influence stability is a key goal in precision medicine. Computational tools to predict stability are widely used, but these tools have limited accuracy due to the low quantity of stability data available for optimizing the models. Here, we will use a new method developed by our lab to measure stability for three million new sequences (>100-fold more than all available traditional stability measurements), then use these data to develop a new accurate predictive model for protein stability. Folding energy landscapes describe the relative energies of all the different conformational states of a protein, including folded, partially folded, and unfolded states. Even when two proteins have similar structures and similar global stabilities, they can have very different energy landscapes, leading to different behavior in biological systems and in therapeutic development. These energy landscapes are challenging to study experimentally and have never been analyzed on a large scale. Our lab recently broke this barrier by developing a new experimental approach to measure these energy landscapes for thousands of proteins in parallel. Here, we aim to extend our method to new, larger protein libraries and improve the level of detail we resolve about each protein’s landscape. Finally, we will use these improved datasets to develop machine learning models to predict energy landscapes.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Injury is the most common cause of death in people 46 years of age and younger. Bleeding from injury (trauma-induced hemorrhage) is the second leading cause of injury-associated death and the most common cause of preventable death. Annually, 70-100,000 Americans suffer a preventable death from trauma-induced hemorrhage. These deaths could be prevented were patients to receive timely care (e.g., hemostatic resuscitation and hemorrhage control procedures within two hours of injury) in hospitals that specialize in injury care (e.g., high level trauma centers). These high-level trauma centers have the equipment, blood products, medications, massive transfusion protocols and staff 24 hours a day, 7 days a week to provide hemostatic resuscitation and hemorrhage control procedures. These resources and services are not available at non- specialized hospitals. Management of bleeding requires timely procedures to stop the bleeding as well as medications and blood transfusions to prevent blood from thinning (trauma-induced coagulopathy). Our previous work demonstrated that the most common reason patients were not quickly transferred (retriaged) from non-specialized hospitals to another specialized high-level trauma center was because clinicians did not know who should be retriaged. There are no national retriage guidelines. Our literature review demonstrated only 22 out of 50 states in the United States have any retriage guidelines. Even among states that have retriage guidelines, most guidelines are very vague (e.g., hypotension requiring blood transfusions). This application’s broad, long-term objective is to improve the timeliness of care of trauma-induced hemorrhage. We propose to comperehensively determine who should be quickly retriaged to specialized high-level trauma centers, and determine if state-of-the-art approaches to informing retriage decisions could improve timliness of treatment and reduce death rates. This study’s first specific aim will identify which patients and injuries have the greatest reduction in death rates upon retriage from non-specialized to specialized high-level trauma centers using Causal Graphical Models. The second aim will understand which patient injury and context attributes multi-speciality injury experts prioritize when making retriage choices using Discrete Choice Experiments. The third aim will determine if a protocol providing retriage decision support [PRotocol for OpMTimal reTRiage [PROMTR)] could improve time to treatment and death rates compared to usual care using Discrete Event Simulation. Upon demonstrating efficacy in improved timeliness of treatment and death rates in this simulation study, our future direction will be implementing and evaluating effectiveness of PROMTR in a Hybrid Type II Cluster Randomized Controlled Trial. This line of research has high potential to improve and standardize existing retriage practices, resulting in the reduction of preventable injury-associated death from bleeding.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This proposal is a new submission of a National Research Service Award for Rheumatology Research Training at Northwestern University Feinberg School of Medicine. The overall objective of this training program is to produce a diverse pool of well-trained scientists with the skills necessary to conduct rigorous and reproducible research in the causes, treatment, and prevention of arthritis, musculoskeletal, and autoimmune diseases. This application comes at a time of substantial and sustained growth in the research enterprise of Feinberg School of Medicine, including within the Division of Rheumatology. This application requests three postdoctoral training positions per year. The training program will be led by Drs. Yvonne Lee and Harris Perlman, who have complementary expertise that spans from clinical medicine to basic science. Drs. Lee and Perlman will be supported by an Internal Advisory Committee and an External Advisory Committee, who will assist in overseeing and monitoring the program to ensure appropriate and timely trainee progress. Trainees will be supported by a mentoring team, including at least one primary research mentor, one secondary mentor, and one data science mentor. The research mentors will be drawn from a diverse pool of 23 well-funded principal investigators, which include faculty from a variety of scientific backgrounds and disciplines, all with a common goal of improving the outcomes of individuals with arthritis and autoimmune diseases. Didactic opportunities include obtaining a Master of Science in Clinical Investigation through Northwestern University’s CTSA-funded, part-time graduate program, which focuses on producing clinical scientists knowledgeable about the complex issues associated with conducting sound, translational and clinical, patient-oriented studies. In addition, our program is attuned to challenges related to recruiting and retaining individuals in scientific careers and will provide a wellness program that assists in work-life balance, financial stability, relationship openness, and future planning. The training program will be supported by a rich and diverse scientific environment, which includes the FIRST-DailyLife Core Center for Clinical Research (NIAMS-funded P30) and the Northwestern University Clinical and Translational Sciences Institute (NIH-funded CTSA). Specific research priority areas include: a) development of organoid models, b) genetic murine models, c) precision medicine in human disease, d) mechanistic/physiologic research, e) outcomes/interventional research, and f) epidemiology/health services research. Through this training program, we expect to nurture bright, well-trained, academically- oriented postdoctoral trainees in their pursuit of a career in rheumatology investigation. By enabling them to synthesize information about the complex issues associated with conducting scientifically and ethically sound research, we will maximize the likelihood that they will be competitive in seeking independent research support, ultimately exerting a sustained influence on the field of rheumatology research.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Motor skill learning, which requires knowledge of body position and real-time feedback of performance, is essential for survival and quality of life. In addition to experiencing general motor deficits due to the loss of dopamine neurons, Parkinson’s patients also experience disruption in motor learning. Dopamine signaling from the substantia nigra pars compacta (SNc) to the dorsal striatum plays a crucial role in mediating motor learning as ablation of dopamine neurons in this pathway renders mice incapable of learning a motor skill task while minimally affecting general locomotion. SNc dopamine neurons that project to the DLS receive various excitatory and inhibitory inputs that can modulate its neuronal activity and its downstream dopamine release. Anatomical studies have shown that the motor cortex (M1/2) directly synapses onto DLS-projecting SNc dopamine neurons, however its functional role remains unknown. In Aim 1 and 2 of this proposal, I will test the hypothesis that M1/2 inputs onto DLS-projecting SNc dopamine neurons undergo synaptic plasticity during motor learning and is able to modulate dopamine release in vivo during motor learning. Although dopamine signaling is required for the acquisition of motor skills, the specific pattern and progression of the dopamine signal over the course of motor learning and how it leads to motor learning impairments remain unclear. In Aim 3, I will link dopamine release dynamics in the dorsolateral striatum (DLS), an area that’s been implicated motor learning and habitual behaviors, to specific kinematics and behavioral features across motor learning using an accelerating rotarod. Findings from these proposed studies will shed light on the neural mechanisms of motor cortical control of motor learning and will have broader implications in movement disorders like Parkinson’s Disease.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Paroxysmal atrial fibrillation (AF) is expected to affect 16 million Americans in 2050. AF is a heavy burden on the healthcare system. The current treatment strategies for AF include catheter ablation, transthoracic cardioversion, and drug therapy. Currently, no method exists for painless and rapid conversion of atrial fibrillation. This proposal features a novel epicardial high- resolution organ conformal electronics low-energy atrial defibrillator for painless AF conversion. In this project, a human-scale, fully implantable organ conformal device for high-definition detection and therapy of AF will be developed. It will be tested and optimized on a large animal model: a canine model of AF induced by high-rate atrial pacing. The endocardial coil-based multi- pulse therapy (MPT) system previously developed in the Efimov laboratory was tested in multicenter clinical trials for atrial fibrillation and ventricular tachycardia treatment. In this grant proposal, the current resolution limitations of MPT will be overcome by (1) incorporating a high- definition organ conformal array of electrodes to sense AF and delivery of MPT over a wide variety of configurations and vectors; (2) deploying MPT on fully implantable battery-free high-definition cardiac biointerface platform; (3) automatic detection of AF paroxysm; (4) machine learning optimized delivery of low energy high-definition MPT to terminate AF paroxysm without delay to prevent atrial pathological remodeling. In summary, rapid termination of AF paroxysm and conversion to normal sinus rhythm will be achieved at painless energy levels by applying state-of- the-art epicardial high-definition mapping and energy-efficient and optimized high-definition MPT delivery.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Bicuspid aortic valve (BAV) is the most common congenital heart defect, and it predisposes patients to complications such as aortic stenosis (AS, most common cause) and aortic aneurysm. BAV patients can develop highly divergent outcomes (e.g., rapid progressive aortic dilatation vs. no long-term complications) but the underlying mechanisms that determine the individual risk for complications are not well understood. There is growing evidence that BAV-based changes in aortic hemodynamics are drivers of aortic wall remodeling and subsequent aortic dilation. A number of studies by our group and others have shown that 4D flow MRI can measure altered aortic 3D hemodynamics in-vivo and has potential to provide better assessments of risk for aortic dilatation in BAV patients. However, current implementations of 4D flow MRI are hampered by long acquisition times (8-15 minutes) and cumbersome manual processing, such as eddy current corrections, noise masking, and 3D segmentations. The goal of this project is to develop an deep learning-based acquisition, image reconstruction, and analyses pipeline for efficient and highly accelerated aortic 4D flow MRI. The first aim of this proposal is development and validation of a highly accelerated 2-point velocity encoding 4D flow MRI with deep learning reconstruction. This will allow enable a 4D flow sequences with low scan times (<2 mins) without sacrificing image quality or hemodynamic accuracy. The second aim will be the development of a deep learning-based automated processing pipeline that will enable rapid processing of aortic hemodynamics and calculation of the wall shear stress dynamics and relative area changes. In the third aim, 20 BAV patients and 20 healthy controls will be recruited from the patient population at Northwestern, then imaged and analyzed using the new protocol. This will demonstrate the utility of using the highly optimized method for the acquisition and analysis of 4D flow MR in a clinical setting. Clinical collaborators will help guide the project to fulfil the ultimate goal of improving clinical imaging and analysis of these complex patients. And Siemen support will help with pulse sequence development and the direct integration of our deep learning network on the scanner, so that this project can be easily integrated in clinical workflows.

NIH Research Projects · FY 2025 · 2025-09

Abstract Precision medicine is rapidly evolving through integrating multi-modal data to tailor treatments and deepen our understanding of diseases like heart failure (HF). Our initiative, HF-ETIOLOGY develops an ethical multi-modal AI framework that harnesses the power of multi-modal data—phenotypic, multi-omic, and socio-behavioral—to identify distinct HF endotypes. Our approach is distinguished by its co-design and iterative development of novel multi-modal AI models for disease endotyping, including advanced Bayesian generative tensor models and temporal tensor models and network medicine approaches. These methods allow us to integrate diverse data modalities and structures, such as longitudinal clinical data and complex multi-omic networks, seamlessly with behavioral and Social Determinants of Health (SDoH) factors. Our project centers around four main objectives: 1) Establish a FAIR-CARE framework to co-design HF- ETIOLOGY data and models; 2) Co-design Generative and Adjustable Prior Bayesian Tensor Factorization (GAP-BTF) to integrate behavioral and SDoH factors with multi-omic network feature learning to identify HF endotypes; 3) Co-design temporal non-negative tensor factorization model (TNTF) to integrate longitudinal phenotypic data while jointly modeling behavioral and SDoH factors for HF endotyping; 4) Identify likely risk genes/targets and pathways and investigate drug repurposing by incorporating SDoH factors for clinically relevant HF endotypes with MAI and network medicine co-design. Central to our methodology is a co-design framework that involves continuous engagement with stakeholders. This collaborative approach ensures that the development of our AI models is informed by clinical insights and aligned with ethical standards, thereby enhancing the practicality and relevance of our research in the clinical setting.

NSF Awards · FY 2025 · 2025-09

With funding support from the Chemical Catalysis program of the Division of Chemistry, Professors Linsey Seitz and Jeffrey Lopez at Northwestern University are investigating fundamental chemistry toward improved hydrogen production via electrochemical water splitting. Hydrogen gas is an important energy carrier and industrial chemical with increasing demand. Proton exchange membrane water electrolysis (PEMWE) is a favorable process for hydrogen production as it has a compact design, minimizes energy losses, and can produce hydrogen at high pressure and purity. However, this technology is expensive, largely due to high loadings of costly platinum group metal (PGM) needed for the process. Widespread PEMWE deployment has not yet been fully realized largely because the development of a commercially viable, stable, and energy-efficient water oxidation catalyst has remained a challenge for decades. The overarching goal of this proposal is to develop and understand the molecular-scale chemistry of inexpensive catalysts that efficiently and durably drive electrochemical water oxidation in PEMWE. This goal will be achieved by designing and implementing advanced automated and experimental probes to characterize catalyst materials under realistic operating conditions in parallel with evaluation of quantitative metrics for structure/performance relationships. Regular meetings with an Industrial Advisory Board will enable critical feedback and guidance to ensure the industrial relevance of ongoing work to the development of PEMWE technologies. In parallel with the research advancements, the PIs will expand electrochemistry-based curriculum at Northwestern University through the development of hands-on laboratory modules to accompany their existing integrated, lecture-based two-course sequence. The combined research and educational efforts will drive novel design and synthesis of efficient and durable catalysts, enhance our understanding of catalytic mechanisms, and develop novel tools and instrumentation for chemical discovery, ultimately advancing the frontiers of chemical science and training a competitive workforce for emerging technologies. Common approaches to catalyst design involve substitution of PGMs or other scarce elements into metal cationic sites of widely explored oxides. Instead, the research team will incorporate inherently Earth-abundant elements into anionic sites creating a library of PGM-free heteroanionic catalyst materials. Tuning the anion dimension of these materials will greatly expand the structural diversity and influence the electronic structure of these materials to offer superior functionality that is inaccessible from chemically simpler homoanionic compounds. The central hypothesis of this proposal is that highly active and durable Earth-abundant water oxidation catalysts can be synthesized and will exhibit enhanced performance through tuning of quantifiable material properties, such as metal valence, anion coordination around metal active sites, and metal cation - anion bond lengths. Along with these material properties, metrics for catalytic activity, material durability, and long-term performance stability will be quantified for every catalyst material tested in this work. The researchers will also exploit material dynamics under controlled reaction conditions to achieve enhanced activity and durability through enhanced fundamental, molecular-level understanding of dynamic catalyst properties. Experimental automation will allow us to perform these carefully designed experiments more quickly and with improved reproducibility, leading to the development of more robust structure-activity and structure-stability descriptors to be identified through our work. Advanced spectroscopic and high throughput analysis will resolve complex catalyst surface reorganization and deactivation mechanisms under controlled reaction conditions. This work will expedite the catalyst discovery and development process to drive transformative enhancements for hydrogen production via PEMWEs based on Earth-abundant catalysts, thereby limiting dependence on scarce and expensive resources. 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 · 2025-09

This project will enable high efficiency conversion of fuels to electricity using a conversion device called a fuel cell. The key components of the fuel cell are the proton conducting electrolyte and the catalysts that facilitate the reaction of oxygen with protons to generate electricity. The project will create advanced electrocatalysts that operate at ~500 degrees Fahrenheit. This temperature is hot enough to accelerate the desired fuel conversion reaction, yet cool enough to slow unwanted material degradation. The research team has previously identified catalyst materials with high activity, but they degrade because they react with the electrolyte in the fuel cell. To address this challenge, the team will utilize ultra-thin barrier layers that are permeable to protons but block the reaction of the catalyst material with the electrolyte. In parallel, they will utilize advanced characterization techniques to reveal the pathway for the reaction of oxygen with protons. This will allow rational design and selection of high activity catalysts. The project will include researchers at various academic levels, and it will support training through internships for high school and undergraduate students, as well as postdoctoral research opportunities for early career professionals. This research aims to design oxygen reduction catalysts suitable for use in solid acid fuel cells. These fuel cells operate at ~ 250 degrees C and incorporate a superprotonic solid acid, cesium dihydrogen phosphate (CsH2PO4) with a proton conductivity of ~ 10-2 S/cm, as the electrolyte. Despite operating at temperatures higher than polymer electrolyte membrane fuel cells, oxygen reduction rates on the Pt catalysts of solid acid fuel cells are relatively low, necessitating the development of alternative catalyst materials. Possible candidates, including Pd and Ag, which show evidence of higher activity than Pt, react with the electrolyte and their activity quickly degrades. The PI proposes multi-layered structures in which proton-permeable barrier layers prevent these detrimental interactions. These structures and the reaction pathways facilitating oxygen reduction will be studied using a suite of tools including X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, and mass spectroscopy of evolved gases, in addition to electrochemical characterization by voltammetry and impedance spectroscopy. These studies are aimed at uncovering the reason for the poor activity of Pt in solid acid fuel cells and enabling rational design and selection of high activity alternatives. 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 · 2025-09

SUMMARY In adults, the generation of new blood vessels is confined to capillaries, where it facilitates tissue growth, remodeling and repair. De novo expansion of the microvascular network occurs through active proliferation and migration of endothelial cells. In contrast, endothelial proliferation in adult large blood vessels, such as arteries, is thought to be rare, except for responses to trauma. We have shown that endothelial injury following physical trauma to the aorta triggers a rapid proliferative response leading to the prompt repair of the inner vascular lining, known as the endothelium. Our preliminary findings indicate that, in addition to physical trauma, chronic inflammation can lead to the demise of endothelial cells in large vessels. We further found that endothelial cell death was associated with a concurrent induction of proliferation, providing a balance between cell loss and renewal that ensures continuity of the endothelial barrier. However, this proliferative response is impaired in aging, creating a deficit in endothelial coverage that results in the deposition of fibrin. These results suggest a previously unrecognized deterioration in the ability of large vessels to maintain adequate regulation of vascular integrity and reveal an unmet need in cardiovascular biology. To this end, we propose experiments to decipher the dynamics, spatial context, and molecular regulators of proliferation in the endothelial lining of the aorta. We used a novel mouse model that precisely titers arterial endothelial cell death. Using this model, we found that proliferation quickly compensates for the lost cells and highlights the important role of endothelial cell proliferation to restore such deficits. The findings also uncovered a remarkable proliferative capacity in the aorta that was previously unrecognized. Importantly, pharmacological blockade of this proliferative activity resulted in organismal death. The findings support the novel concept that ongoing proliferative repair of large vessel endothelial cells is an essential and previously unsuspected biological function. These data prompted several questions: What is the proliferative capacity of aortic endothelial cells? What stressors mediate cell death in the aortic endothelium? Is the reserve proliferative capacity of the endothelium impacted by metabolic alterations associated with common comorbidities (hyperlipidemia, diabetes) or oxygen-reperfusion events? Energized by these questions and our robust preliminary data, we hypothesize that Endothelial cells of the aorta retain a significant proliferative reserve that is continuously available for repair. This capacity is restrained by metabolic comorbidities that limit vascular resilience and cell-cycle entry. Two aims were developed to test this hypothesis: (1) To characterize the proliferative reserve of endothelial cells in the aorta. and (2) To determine whether metabolic comorbidities impact aortic endothelial proliferative resilience. These broadly defined aims have been conceptualized to fill gaps in our knowledge of fundamental processes in endothelial cell biology and to exploit this information for mechanistic studies and medical applications.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Ca2+ release-activated Ca2+ (CRAC) channels are highly Ca2+-selective ion channels critical for regulating Ca2+ homeostasis and signal transduction in many cells. These channels are activated in response to the depletion of endoplasmic reticulum (ER) Ca2+ stores and are expressed in both excitatory and non-excitatory cells. Mutations in CRAC channel genes have been linked to severe immunodeficiencies, autoimmunity, and debilitating myopathies, underscoring their physiological significance. CRAC channels are composed of two proteins: Orai, the pore-forming protein in the plasma membrane, and STIM1, an ER-resident protein that activates Orai upon Ca2+ store depletion. Despite significant progress, the structural mechanisms underlying Orai activation remain poorly understood. A previous study revealed the structure and architecture of the wild-type, closed state structure of the Drosophila melanogaster Orai (dOrai), showing a hexameric assembly with concentric transmembrane domains that surround a central pore. However, the structural details of the open state, including the conformation of pore-lining residues and the intracellular domains, remain unresolved. A 2020 cryoEM structure of a constituently open dOrai mutant offered preliminary insights into the open channel structure but suffered from poor resolution and constraints imposed during the sample preparation. As a result, fundamental questions about the structure and conformation of the channel in the open configuration persist. In this proposal, I aim to address these gaps using structural techniques and functional approaches to study the mechanism of CRAC channel activation and inhibition by CRAC channel antagonists. In Aim 1, I will use cryoEM to analyze the structures of three well-studied dOrai open mutants which we hypothesize represent different intermediate open states within the dOrai gating cycle. In Aim 2, I will study the effects of specific inhibitors on the structure of dOrai and identify their binding sites. I will further extend the structural results by functionally validating the binding sites through molecular dynamic simulations and electrophysiology studies. Insights gained from these structures will advance our understanding of CRAC gating and aid future mechanism- based drug discovery efforts targeting CRAC channels.

NSF Awards · FY 2025 · 2025-09

Non-Technical Abstract Active matter—systems composed of self-propelled particles such as bacteria or synthetic microswimmers—can behave in surprising ways when confined. For example, particles that move randomly in open space may exhibit organized, collective motion when enclosed. This project explores what happens when active particles are confined within a soft, flexible boundary like a droplet. The research team recently discovered that this setup leads to unexpected behaviors: the droplet itself spontaneously moves and deforms, driven by the activity inside. By combining theoretical modeling with controlled experiments, the investigators aim to uncover how particle motion and boundary softness interact to produce complex dynamics. Insights from this work could inform new approaches for microscale transport and control, with potential applications in soft robotics, environmental sensing, and targeted drug delivery. The project also supports interdisciplinary student training and public outreach through visually compelling experiments that mimic living systems, contributing to the growth of the STEM workforce and furthering NSF’s mission to advance scientific innovation. The project is committed to creating opportunities that are accessible to all Americans, without preference or exclusion of any individual or group. Technical Abstract This project investigates the collective dynamics of active colloidal particles confined within soft, deformable boundaries. While rigid confinement is known to strongly influence active matter behavior, the effects of soft, responsive boundaries remain poorly understood. Recent discoveries by the PIs show that Quincke rollers—synthetic self-propelled particles—encapsulated in droplets can deform the interface and drive spontaneous droplet motion, revealing a novel feedback loop between internal activity and boundary mechanics. The proposed work combines controlled experiments with theoretical modeling to explore how particle properties (e.g., density, propulsion speed, locomotion type) interact with soft confinement. Experimental observations will be complemented by microhydrodynamic models that couple particle dynamics with interfacial mechanics to uncover the physical mechanisms underlying shape changes and emergent motility. This research will advance fundamental understanding of soft active matter and may inform the design of autonomous microscale transport systems for applications in medicine, sensing, and soft robotics. The project emphasizes interdisciplinary training in theory and experiment, including collaborative opportunities at national laboratories, and supports workforce development through public outreach and engagement. 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 2025 · 2025-09

PROJECT SUMMARY The ovarian follicle, comprised of an oocyte surrounded by somatic granulosa and theca cells, is the functional unit of the ovary. Folliculogenesis, the process of follicle growth, is highly dependent on bi-directional communication between the granulosa cells and the oocyte to promote oocyte growth, survival, and quality. Individuals are born with a non-renewable source of follicles, indicating a need for tight regulation of follicle activation and growth to prioritize the removal of poor-quality oocytes and the fertilization of high-quality oocytes that give rise to the next generation. The cGAS-STING pathway is a mediator of the innate immune response and functions by detecting cytosolic dsDNA and eliciting an inflammatory response. Through RNA in situ hybridization, we have shown that the machinery for the cGAS-STING pathway is present in intact preantral follicles with distinct localization. cGAS mRNA is enriched in the oocyte, and STING mRNA is predominantly in the granulosa and theca cells. Importantly, cGAS expression increases significantly in the oocyte between the primary and secondary follicle stages. Our overarching hypothesis is that the cGAS-STING pathway functions as an active surveillance mechanism to regulate the removal of poor-quality oocytes from the active growing pool. This prevents damaged oocytes from being fertilized and contributing to the next generation. I will utilize three validated cGAS-STING pathway inducers: Q-VD-OPH/ABT-737, MC-LR, and diABZI to selectively activate different components of the pathway and study the downstream consequences. We expect that pathway activation will cause granulosa cells to acquire an inflammatory signature, which disrupts bi-directional communication due to altered granulosa cell function and compromises oocyte quality and survival. In Aim 1, I will test different pathway inducers to investigate follicle survival and growth, and oocyte quality in an in vitro encapsulated follicle growth system, as well as the downstream inflammatory response through western blots, immunofluorescence, ELISAs and single-cell RNA-Seq compared to vehicle-treated control follicles. In Aim 2, I will isolate follicle compartments to study pathway responsiveness and utilize cGAS and STING knockout mice to generate reconstituted chimeric follicles to further determine the cell-type specific function and responsiveness of cGAS and STING when treated with pathway inducers. This proposal will elucidate the function of the cGAS-STING pathway in ovarian follicles and determine whether its modulation regulates removal of poor-quality oocytes from the active growing pool. This work may provide novel mechanistic insight into how follicles respond to environmental exposures such as MC-LR. Overall, the comprehensive intellectual infrastructure of Northwestern’s Center for Reproductive Science and Northwestern’s Feinberg School of Medicine and my interdisciplinary mentoring team spanning cGAS-STING biology, genomic instability, toxicology, and reproductive science will provide me with the support and unprecedented skillsets to mature into an independent scientist investigating at the interface of reproductive science and public health.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Violence exposure is a major risk factor for depression across development, with depression severity rising steeply during early adolescence, and especially among females. Threatening events such as violence exposure may be especially impactful for females because they perceive future threatening events as less controllable than males. In line with this perspective, researchers have shown that rumination mediates the association between exposure to uncontrollable stressors and hopelessness among urban adolescent girls, but not their male peers. Further, activity in areas of the brain responsible for threat processing respond more to threatening stimuli among women who have experienced more violence, while previous violence exposure does not modulate males' responses to threatening stimuli. It is unclear, however, threat differentially impacts brain networks across the sexes. One network that could help explain sex differences in response to threat is the salience network (SN). The SN is important for reorienting to unexpected stimuli that are behaviorally relevant, and as such, is often investigated in the context of threat and fear learning paradigms. Violence exposure has been shown to be associated with greater connectivity within the SN, and increases in within SN connectivity have been found to mediate the asso- ciation between abuse and depression during adolescence. Notably, the SN physically occupies a greater portion of cortex in females and those with depressive disorders. Being exposed to threatening experiences may result in utilizing more cortical tissue for evaluating the salience of stimuli, considering experience impacts the expanse of associated brain networks. Therefore, threat may be associated with altered SN properties. Properties of the SN may also change during adolescence, as extinction retention increases for male rats over adolescence, while it decreases for females. Importantly, this project proposes an integrative biopsychosocial model of sex differences on depression in response to threat across development, investigating properties of the SN as potential mecha- nisms. To address sex differences on SN properties in response to threat across development, I will utilize a new method to define personalized brain networks, which is essential for estimating the expansiveness of networks. This method employs an empirical Bayesian framework by using group templates as priors, allowing for efficient and reliable estimates of individual vertex-level network membership. To maximize the power to detect effects, I will combine data from two active R01s awarded to my primary sponsor, Dr. Nusslock, that together are col- lecting data from 620 adolescents ages 14-18, each with three neuroimaging sessions spaced a year apart, and threat exposure and depression symptoms measured concurrently with the neuroimaging sessions. In order to execute this research, I have assembled an interdisciplinary mentorship team that will help me expand upon my knowledge of developmental affective neuroscience (Nusslock, Insel), youth trauma (Suárez), and personalized networks and statistics (Mejia, Samia).

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract In addition to the typical retrovirus genes for viral genome replication, integration, and virus maturation, the genome of human immunodeficiency virus-1 (HIV-1) encodes four unique accessory genes. Although not directly involved in the viral genome replication or virus assembly, these HIV-1 accessory proteins play critical roles in maintaining the infectivity of the virus, particularly in the late stages of the HIV lifecycle. During HIV-1 infection, they establish numerous physical interactions with host factors; and typically promote virus infection by intercepting essential host cellular processes, such as antiviral immune response. Some key targets of these HIV accessory proteins have been identified for 20 years, yet the atomic details about their interactions have been elusive for most of them due to the challenges of determining structures of large and labile complexes involving proteins and nucleic acids with traditional structural biology methods—either X-ray crystallography or NMR. Recent advancements in cryogenic electron microscopy (cryoEM) have opened opportunities to analyze these challenging complexes involving HIV-1 accessory, host regulatory proteins, and nucleic acids. For example, recent studies from our groups and two other groups have revealed the mechanistic basis for the HIV-1 accessory protein Vif that hijacks the host ubiquitin ligase to degrade human APOBEC3G antiviral restriction factors in the host T-cells. However, much of HIV-host interaction networks remain uncharacterized. My long-term career aspiration is to become an independent structural biologist with a primary focus on HIV, and contribute to humanity’s yet-to-be fulfilled goal of curbing the devastating AIDS pandemic through rational drug design. This K22 career development proposal outlines a 2-year independent research plan to study the structural basis of HIV accessory proteins Vpr and Vif with known and unknown host factors that they associate with. I have taken advantage of—and will continue to benefit from—the fantastic infrastructure afforded by the UCLA-AIDS institute and learned cutting-edge cryoEM technologies in the Zhou laboratory in UCLA’s California NanoSystems Institute. In Aim 1, I will focus on the previously identified yet structurally uncharacterized important protein complexes involving HIV-1 Vpr and Vif by targeted in vitro reconstitution approaches. In Aim 2, I will apply Dr. Zhou lab’s novel cryoID approach (a cryoEM-based structural proteomics method) to explore and identify novel host interactors of Vpr and Vif. This approach involves the enrichment of the endogenous protein complexes directly from HIV-infected cells for atomic structure determination. Overall, this K22 project would not only bring cutting-edge technologies to bear on challenging HIV/AIDS research, but would also define intricate strategies that HIV adopts to combat host anti-viral factors and to exploit pro-viral factors. The atomic structures from the proposed studies will form the basis of my future R01 grant focusing on structural biology of HIV-host interactions and structure-guided development of antiretroviral therapeutics.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY Progressive loss of kidney function in chronic kidney disease (CKD) is associated with adverse clinical outcomes including inflammation, anemia, and bone and mineral disorders that contribute to cardiovascular events and increased mortality. Limited knowledge of molecular mechanisms that contribute to CKD progression impedes development of desperately needed therapeutics aimed at reducing morbidity and mortality in patients with CKD. Expression of hepatocyte nuclear factor 4 alpha (Hnf4α) is dramatically reduced in bone and kidney from patients and animals with CKD, but the role of HNF4α in CKD progression and CKD-associated outcomes is unknown. In preliminary data for this project, we establish that deletion of Hnf4α in osteoblasts results in bone loss and we demonstrate that inflammation is a strong suppressor of Hnf4α expression in bone. We show that HNF4A2 regulates the expression of Pth1r in osteoblasts and that HNF4A deficiency contributes to PTH hyporesponsiveness in CKD. In additional preliminary data, we show that osteoblast HNF4α provides a major niche for erythropoiesis by inducing the secretion of EPO from osteoblasts. Consequently, osteoblast deletion of Hnf4α aggravates iron deficiency anemia. We demonstrate that similar reductions in bone HNF4α in patients and animals with CKD result in impaired osteogenesis and that overexpression of Hnf4α2 in osteoblasts of mice with CKD corrects PTH response, skeletal and erythropoietic abnormalities. We further show that Hnf4α is reduced in the kidney of patients and mice with CKD, and that inhibition or genetic deletion of kidney HNF4α induces fibrosis and accelerates CKD progression. We also show that hyperphosphatemia and resulting inflammation suppresses Hnf4α via a STAT3 mediated mechanism. In final preliminary data, we demonstrate that rescue of HNF4α signaling in the kidney delays CKD progression and propose the reconciling hypothesis that multiorgan HNF4α deficiency contributes to ROD, anemia and CKD progression. In Aim 1, we will establish that inflammation suppresses Hnf4α in bone leading to a feed-forward loop, whereby reduced Hnf4α amplifies the inflammatory signaling, and induces PTH hyporesponsiveness. We will demonstrate the protective role of HNF4α in bone by genetically inducing and suppressing Hnf4α2 expression in pre- osteoblasts in mice receiving anabolic PTH challenges and in mice with moderate or advanced CKD. In Aim 2, we will investigate HNF4α as a regulator of osteoblast-induced bone marrow erythropoiesis via EPO, using deletion and overexpression of Hnf4α in osteoblasts, in co-cultures with hematopoietic precursors in presence and absence of EPO, in vivo in two established models of anemia, i.e. iron deficiency anemia and anemia of inflammation, and in CKD. Finally, in Aim 3 we will investigate the critical role of kidney HNF4a in CKD progression and STAT3 as an upstream regulator, using mice fed a high phosphate diet and the Col4a3KO mouse model of CKD. Finally, we will demonstrate the protective role of HNF4A in the kidney by genetically overexpressing Hnf4α in the proximal tubules in mice with early, moderate and advanced CKD.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Mitochondrial dysfunction is a well-established cause of neurologic and psychiatric disease. The brain is the body’s most energetically demanding tissue and is especially vulnerable to metabolic challenges such as hypoglycemia, ischemia, and mitochondrial disease. One such mitochondrial disease is caused by defects in the mitochondrial enzyme MDH2, which catalyzes the final step in the TCA. Patients with mutations in MDH2 develop infantile encephalopathy and epilepsy. The association between mitochondrial dysfunction and neurologic disease is often attributed to a deficiency in ATP. However, in addition to ATP, the mitochondrial TCA generates biosynthetic intermediates like α-ketoglutarate (α-KG) which is used to synthesize the neurotransmitter gamma- aminobutyric acid (GABA). GABA is the brain’s primary inhibitory neurotransmitter, and decreased GABA signaling underlies neurologic and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, autism spectrum disorder, and epilepsy. The research proposal aims to elucidate the critical role of mitochondrial MDH2 in ATP and GABA production within GABAergic neurons. The hypothesis predicts that MDH2-deficient GABAergic neurons can produce adequate ATP through glycolysis but fail to synthesize GABA, leading to impaired GABA signaling without neuron death. The proposal tests the hypothesis with two specific aims. The first aim investigates whether MDH2 is essential for ATP production in GABAergic neurons. This involves studying the bioenergetic consequences of MDH2 loss in human iPSC-derived GABAergic neuron cultures and a mouse model with MDH2 selectively knocked out in GABAergic neurons. The second aim explores the necessity of MDH2 for GABA synthesis using techniques such as metabolomics, RNA sequencing, isotope tracing, and spatial metabolomics. Additionally, the proposal examines the potential of α-ketoglutarate (α-KG) as a supplementary substrate for GABA synthesis to mitigate MDH2 deficiency. This research seeks to uncover the metabolic requirements for GABAergic signaling, providing insights into the connection between mitochondrial dysfunction and GABA-related diseases, and paving the way for new therapeutic strategies targeting GABAergic neuron metabolism.

NIH Research Projects · FY 2025 · 2025-09

Acute myeloid leukemia (AML) is a hematologic cancer with a generally poor prognosis, and mutations in TP53 define one of the most adverse risk molecular subsets. National and co-operative group datasets suggest that sociodemographic characteristics (social deprivation index, education, poverty, insurance) influence survival in AML. We established the multi-institution Chicago AML Registry that has collected demographic and clinical data on 822 AML patients. In our published analysis, composite census tract-based socioeconomic measures of disadvantage and affluence were found to be potent mediators of observed AML survival differences. These tract-based measures may be markers for specific aspects of patients’ social and physical environments (SPE) that contribute etiologically to poor AML outcomes. Our preliminary data confirms an increased prevalence of adverse genomic characteristics in AML patients living in adverse SPE, specifically TP53 mutations and complex cytogenetic abnormalities. In Aim 1 we will develop a neighborhood stress scale, incorporating area deprivation index and gun violence data, and link this to adverse genomic characteristics of AML as well as more distal outcomes including treatment response and relapse-free and overall survival. We also develop a prospective study of preleukemic patients bearing small clones of TP53 mutated hematopoietic stem cells and examine the effects of self-reported social stress on inflammation and clonal evolution. We next address mechanisms by which factors within the SPE drive TP53 mutant clonal expansion. Our preliminary data confirm that an increased burden of social stressors results in activation of the innate immune system. Leveraging models of social stress in transgenic murine models of mutant TP53 Clonal Hematopoiesis, as well as serial patient samples we will study dynamic interactions between social environment, ancestry, and clonal trajectories in AML. Importantly, our analyses will consider both self-identified race/ethnicity (SIRE) and genetic ancestry based on ancestry informative markers (AIMs) to appreciate the overlapping, but independent effects of social constructs and genetic ancestry that may influence inflammation and immune response. Our preliminary studies suggest that the NLRP1 inflammasome/IL-1β axis may represent a mechanistic link between social stressors and TP53 mutant clonal evolution and we will develop xenografts from AML patients from a range of social backgrounds to determine the therapeutic impact of targeting the NLRP1 inflammasome/IL-1β axis. The goal of this project is to triangulate registry data, patient samples and animal models to establish social stress as a biologic determinant of clonal trajectories in AML development.

NSF Awards · FY 2025 · 2025-09

This project investigates an approach for managing the radio spectrum that is fundamentally different from today. A new approach is needed because of high congestion of the limited airwaves caused by growing demand from all sectors of society. The project combines analysis of an innovative regulatory model, based on assigning rights to receivers compared to today’s approach of licensing transmitters, with development of innovative technical solutions for automatic spectrum management and peer-to-peer cooperation within the context of that regulatory model. The goal of the new approach is to increase total wireless capacity, enable a wide range of applications, assure spectrum access for the common good, and promote innovation. The project has three interrelated research thrusts grounded in case studies of the 7-8 GHz and 12 GHz bands. The first thrust investigates how a receiver-centric rights regime should be structured to minimize transaction costs, encourage sharing, and discourage hoarding of spectrum resources. The second thrust develops watermarking techniques that enable interference victims to robustly identify the operator responsible for the interference. Two techniques are developed and evaluated, one that is universal and one that is tailored for the orthogonal frequency division multiplexing (OFDM) physical layer commonly used in modern broadband. Rapid identification of the operator responsible for interference is essential in the envisioned new spectrum regime to facilitate coordination, negotiation, and trading. The third thrust explores fault-tolerant protocols and a distributed ledger system for peer-to-peer cooperation among spectrum users to automate rights registration, monitor usage, and facilitate spectrum trading under the envisioned new spectrum regime. These mechanisms enable decentralized spectrum management approaches that evolve more quickly and achieve better reliability and resilience than today’s centralized monolithic solutions such as the Citizens Broadband Radio Service Spectrum Access Systems. 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 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT As the global population ages, the prevalence of Alzheimer’s disease and related dementias (ADRD) is on the rise. This poses significant challenges to healthcare systems worldwide. Primary Progressive Aphasia (PPA) is a clinical ADRD dementia syndrome characterized by progressive decline in comprehension and expressive language skills. While the primary approach for addressing language and communication impairments in PPA involves non-pharmacological intervention administered by a speech-language pathologist, access to care can be difficult due to a limited number of clinicians and lack of evidence-based interventions. While technology- supported interventions have the potential to improve access to care, promote social participation, ameliorate communication skills, and improve emotional well-being, there has been no systematic exploration of how individuals with PPA and related dementias use web applications. This study will address this gap by conducting a comprehensive analysis of an existing web application used in the Communication Bridge-2 randomized controlled trial (RCT), to provide insights into the usage, feasibility, and usability of such technologies in supporting communication for individuals with PPA and related dementias. Aim 1 will establish practical use guidelines for the existing web application. We will analyze retrospective app user data and post- study interview transcripts from Communication Bridge-2, an NIH stage 2 RCT of speech-language therapy for PPA. We will categorize user groups (frequent vs. nonfrequent users) and determine which clinical and demographic factors (e.g., sex, age, aphasia severity) correlate with greater app engagement. This will allow us to determine which groups are using the app vs. which are not and may require additional engagement strategies. For Aim 2, we will identify evidence-based steps to optimize the existing app for a broader audience of PPA and related dementias. Through semi-structured interviews with individuals with PPA and their communication partners, we will identify implementation barriers to technology-supported intervention and propose necessary changes to improve user engagement. This will allow us to evaluate what app features users like, to identify app limitations, and to propose modifications to the app to improve user experience in this population. This project will occur within the Healthy Aging & Alzheimer's Research Care Center at the University of Chicago, where I will work with data from the only large-scale RCT for language and communication in PPA, as well as individuals with PPA referred from around the world. Findings have the potential to optimize technology use to maximize communication skills, quality of life, and overall care for those within the ADRD spectrum.