Northwestern University

NIH Research Projects · FY 2025 · 2025-09

Voice disorders affect 12-35% of the population over 60 years of age, causing significant health, psychosocial, and occupational consequences. The cause of age-related changes in voice quality, known as presbyphonia, is multifactorial including muscle atrophy and reduced muscle strength capacity. Voice therapy is the first line of recommended treatment for presbyphonia, yet two-thirds of older patients do not show improvement with voice therapy. To date, there are no objective physiological measures of vocal muscle strength to evaluate the effectiveness of voice therapy in older adults. Here, we propose establishing the first outcome measure to assess vocal muscle strength capacity. Physiologically, anaerobic systems generate the energy needed for muscle strength, with blood lactate (La-) as a byproduct. Blood La- is routinely used pre- and post- exercise to evaluate changes in limb anaerobic muscle strength. Preliminary studies have found that an adapted 60-second laryngeal diadochokinetic task (LDDK) resulted in a significant increase in blood La-, demonstrating that this vocal task requires demand of anaerobic energy systems. Given that direct study of human vocal musculature in vivo is impractical, we hypothesize that measuring blood La- is a novel and practical approach to assessing vocal muscle strength capacity. This proposal will establish validity, the extent an outcome tool captures what it is intended to measure, of a vocal demand task outcome measure of vocal muscle strength. We will recruit healthy voice participants and patients over 60 years with presbyphonia from the Northwestern Memorial Hospital Voice Clinic. In healthy voice participants, to establish construct validity, Aim 1(a) will identify the point within a 2-minute window of completing three vocally demanding tasks (LDDK, Loud Sustained Phonation, Loud Oral Reading) that elicits the largest increase in blood La- from resting levels to establish the most anaerobically demanding task (construct validity). Aim 1(b) will compare vocal demand-induced changes in blood La- with age. We hypothesize that LDDK will result in the largest increase in blood La- concentration and the rate of blood La- increase will be smaller for older adults compared to younger adults for LDDK. To establish criterion validity, Aim 2 will determine the association between vocal muscle strength capacity and limb muscle strength capacity in patients over 60 years of age with presbyphonia, to establish if there is a correlation between our hypothesized LDDK measure of vocal muscle strength with an already established measure of limb muscle strength (criterion validity). We hypothesize that diminished LDDK function correlates with reduced limb muscle strength in older adults with presbyphonia. This innovative proposal will establish the first known quantitative vocal muscle strength task, from a physiological perspective, —an outcome measure that addresses goal 1 of NIDCD’s Theme 5. The findings from this proposal will provide an essential foundation for a subsequent R01 that will apply the novel biomarker and vocal demand task outcome measure to evaluate the anaerobic vocal muscle strength changes that occur during various voice therapy programs designed for treating the aging voice.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT An interruption in the normal swallowing mechanism due to abnormal neuromuscular function in the esophageal body or the lower esophageal sphincter (LES) is associated with significant morbidity and quality of life impact, as well as increased mortality related to malnutrition, aspiration and cancer. Achalasia is the prototypical esophageal motility disorder and has an incidence of 1-5 per 100,000 and a prevalence of 10-20 per 100,000. Unfortunately, the cause of achalasia is unknown and the current therapies are primarily compensatory in nature and focus on disrupting the LES to improve emptying using either endoscopic dilation or surgical myotomy. Over the last 5 years, there has been an evolution away from dilation and surgery toward peroral endoscopic myotomy (POEM) due to its less invasive approach compared to surgery and its superior efficacy compared to dilation. However, important questions regarding the effectiveness and risks of POEM remain and the impact of the myotomy approach (position, length, depth) on outcomes is also unclear. The standard POEM myotomy is typically 8-10 cm in length, extending 2-3 cm into the cardia and approximately 6-7 cm above the squamocolumnar junction and it is performed with either a transmural or superficial approach targeting only the circular muscle. We recently reported that blown out myotomy (BOM) is a common mechanism of achalasia treatment failure related to focal dilatation along the myotomy site that profoundly impairs emptying. The scientific premise of this study is that the current arbitrary approach to myotomy in POEM is associated with a predilection to increased GERD and BOM formation through its effects on the distal esophagus. We hypothesize that an innovative precision approach with POEM can improve outcomes and reduce complications. Thus, we are proposing a multicenter randomized trial (Aim 1) to test the hypothesis that a short, tailored POEM will be non-inferior to the standard POEM and associated with less reflux disease and a reduction in BOM formation. Additionally, we will also aim to better understand outcomes in jackhammer esophagus and spastic motility disorders through a rigorous prospective study (Aim 2) assessing response to a long tailored myotomy. Using data and samples from study participants, we also aim to refine and validate a new Achalasia Patient Reported Outcome (APRO) measure (Aim 3) and establish a repository of biological specimens to help elucidate the pathophysiology of achalasia. This study will reshape the management of esophageal motility disorders and improve our understanding of the pathogenesis of these disorders by sharing specimens with translational scientists focused on neurogastroenterology.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT: KMT2D is subject to a high frequency of recurrent somatic mutations in many cancers, most notably bladder cancer (BLCa), and nearly 40% of KMT2D mutations lead to truncation or other major alteration of its product, the COMPASS monomethyltransferase MLL4. However, the tumorigenic mechanisms specific to MLL4 truncation have yet to be fully elucidated. The preliminary and published studies presented here reveal that truncated MLL4 consistently re-localizes from the nucleus to the cytosol, indicating the potential for non-canonical tumorigenic mechanisms arising from MLL4 truncation mutations, which could involve loss of catalytic-independent MLL4/COMPASS functions or a potential gain of function for truncated MLL4 in the cytoplasm. Importantly, cytoplasmic MLL4 is readily detectable in bladder tumors with MLL4 truncation. The goal of this application is therefore to accomplish three specific Aims: 1. Define the molecular mechanisms by which MLL4 truncation mutation and relocalization to the cytosol alter MLL4/COMPASS function to drive tumorigenesis, 2. Develop MLL4 mutation status and cytoplasmic localization as predictive biomarkers for patient stratification and targeted therapy in BLCa, and 3. Evaluate the impact of MLL4 mutation on response to pemetrexed treatment using in vivo animal models and patient-derived ex vivo models of MLL4/COMPASS- mutated BLCa. In Aim 1, we build upon preliminary findings of genomic instability due to transcriptional dysregulation in SET-deleted and UTX KO cells to propose ChIP-seq analysis of differential chromatin occupancy for nuclear MLL4/COMPASS factors such as UTX, with RNA-seq for associated differential gene expression, in isogenic MLL4 truncation vs WT cell lines. Based on preliminary findings of interaction between truncated MLL4 and the de novo nucleotide synthesis enzyme PAICS, we also propose to employ mass spectrometric analysis of MLL4 purified from these isogenic lines to identify and characterize novel, cytoplasmic protein interaction partners of truncated MLL4. These studies have the potential to deliver MLL4 truncation- specific targets for small molecule disruption, enabling development of targeted cancer therapies. In Aim 2, we propose to establish the association of cytoplasmic MLL4 IHC staining with MLL4 truncation mutation status in BLCa patient samples and perform a retrospective study exploring the potential use of MLL4 mutation status in BLCa for predicting responsiveness to the methotrexate-containing chemotherapy MVAC. These applied studies have the potential to enable patient stratification and informed treatment decision-making, advancing progress towards individualized BLCa treatment. In Aim 3, we build upon our recently reported finding of a targetable de novo nucleotide synthesis dependence in MLL4-mutated cancers, proposing studies to evaluate BLCa sensitivity to the de novo nucleotide synthesis inhibitor pemetrexed in vivo and to further evaluate MLL4 mutation-specific responsiveness to pemetrexed in autochthonous mouse and patient-derived organoid models of BLCa. These pre-clinical studies have the potential to support future clinical trials of targeted therapies for MLL4-mutated BLCa.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Tissue engineered vascular grafts (TEVGs) are a promising alternative to autologous tissues, yet none have been clinically approved for small-diameter revascularization due to pathological remodeling. Our lab previously showed TEVGs made from decellularized arteries had severe calcification which was associated with vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and oxidative stress. We are now developing TEVGs resistant to calcification using matrix metalloprotease - degradable polyethylene glycol hydrogels (MMP- PEG) to coat the adventitial surface of decellularized aortas. This approach enables us to manipulate various aspects of TEVG adventitia remodeling including angiogenesis, innervation, and immunomodulation. As a proof-of-concept of our novel TEVG design, this project seeks to determine the effect of vasa vasorum neoangiogenesis in TEVG remodeling and to ascertain whether promoting angiogenesis is a feasible approach to improve TEVG remodeling. We hypothesize that robust vasa vasorum angiogenesis will reduce TEVG calcification by reducing osteogenic differentiation of cells in the vascular wall. We will test this hypothesis through two Aims. In Aim 1, we will utilize IPSC technology and PEG hydrogels to study the vasculogenic potential of MSCs, one of the main cells involved in vasa vasorum angiogenesis and vascular remodeling, derived from peripheral artery disease patients in 3D. The knowledge generated in this aim will provide insight into the regenerative potential of diseased patients and guide the design of biomaterials suited to promote adventitia angiogenesis, specifically the ideal mechanical stiffness and choice of pendant peptides in our PEG hydrogels. In Aim 2, we will evaluate the impact of vasa vasorum angiogenesis using TEVGs coated with angiogenic PEG hydrogels. Apart from a new approach to improve TEVG remodeling, the findings from this project will provide new insights into the role the vasa vasorum in vascular disease and yields a new technology that can be extended to autologous grafts and periadventitial therapies. Ultimately, this project has the potential to improve healthcare and quality of life of patients with cardiovascular disease thereby fulfilling the mission of the NHLBI.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Cholesterol concentration in the blood is one of the primary determinants of coronary heart disease (CHD) events. Human apolipoproteins (APO) serve as binding ligands as well as cofactors for enzymatic interactions that mediate cholesterol metabolism. Apolipoproteins are also central to the pathobiology of atherosclerosis through direct effects on lipid metabolism as well as atherosclerosis initiation, propagation, inflammation, and plaque instability. Human APOs are frequently post-translationally modified, which alters protein function and human phenotype. For example, post-translational modifications (PTMs) such as glycosylation of apoB may increase the synthesis and excretion of apoB lipoproteins and lead to adverse cholesterol profiles. Our prior work strongly suggests that PTMs of human APOs may be a biologic pathway through which adiposity and insulin resistance modify cholesterol concentrations and downstream CHD events. Further, preliminary data from our group indicates that the relative abundance of APO PTMs in atherosclerotic plaque varies substantially from APO PTMs found in plasma, suggesting that PTM of human APOs may partially mediate of atherosclerosis propagation. Our group has identified 18 PTM’s of apoA-I, 9 of apoA-II, 2 of apoA4, 32 glycosylated PTMs of apoB-100, 13 of apoC1, 14 of apoC2, and 23 of apoCIII, and 18 of apoE. However, we have not quantified the associations of these APO PTMs with adiposity, insulin resistance, downstream atherogenic lipid concentrations and CHD events. Nor have we comprehensively characterized APO PTMs found in atherosclerotic plaque and plasma. Therefore, the overall objective of this study is to characterize the full spectrum of APO PTMs in human plasma and to quantify their associations with upstream adiposity and insulin resistance and downstream atherogenic lipid levels and CHD endpoints (fatal/non-fatal MI) in the population-based Multi-Ethnic Study of Atherosclerosis Cohort. We will also explore differences in APO PTMs across paired samples of human carotid and femoral atherosclerotic plaque and plasma. Characterization and cataloguing of apolipoprotein PTMs and understanding their associations with prior exposures to adiposity and insulin resistance and subsequent lipid levels and CHD endpoints will lead to novel insights into lipid metabolism and atherogenesis and may provide novel targets for therapy.

NSF Awards · FY 2025 · 2025-09

This five-year CAREER grant will investigate how to design an after-school mathematics space within a school setting that can challenge and expand both students' and teachers' conceptions of what doing mathematics means and teach them to see participation in the discipline in increasingly nuanced and expansive ways. Informal learning contexts can encourage engagement by allowing students opportunities to choose their own activities and provide a playful environment. The study focuses on designing an after-school program to support recreational mathematics activities for elementary students. At the same time, teachers who are supporting the after-school program with students will have the opportunity to learn to notice different forms of mathematical participation and learning. The program will serve to help teachers and students see mathematics as creative and joyful - as something people might choose to do. This design-based study, situated in two elementary school sites, seeks to iteratively design a community of practice for doing mathematics that expands both teachers' and students' capacity to recognize and value a broad range of mathematical participation and interest. Teachers will have the opportunity to engage in the after-school program and learn about different forms of mathematical engagement and activity. The project will identify design features, principles, processes, and underlying theory that contribute to expanding students' understanding of and participation in mathematics. Similarly, the project will also contribute to developing teachers' curiosity about student thinking and their capacity to notice mathematical participation in nuanced ways. A teacher professional learning community will meet regularly to investigate, discuss, and plan what is happening in the after-school program. The data collection will focus on documenting both students' experiences in the recreational mathematics program and teachers' perceptions of students' mathematical thinking. Data collected include teacher and student interviews, video of the after-school program and the professional learning community, student-created artifacts of mathematics, and field notes. The iterative, multi-layered analysis will examine how the learning environment is designed and developed over time. The Discovery Research preK-12 program (DRK-12) is an applied research program that seeks to significantly enhance the learning and teaching of science, technology, engineering, and mathematics (STEM) by preK-12 students and teachers. Projects in the DRK-12 program build on fundamental research in STEM education and prior research and development efforts that provide theoretical and empirical justification for funded projects. This project is also supported by the AISL program, which seeks to advance new approaches to, and evidence-based understanding of, the design and development of STEM learning in informal environments. This includes providing everyone multiple pathways for accessing and engaging in STEM learning experiences. 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 Sexual minority (SM) individuals (e.g., lesbian, gay, bisexual) are considered at higher cardiovascular disease risk due to the discrimination based on sexual orientation. Experiences of discrimination including internal and interpersonal discrimination have led to higher rates of risk factors like smoking, binge drinking, and substance use compared to straight adults. Additional studies have also suggested issues in health care access and quality of care and that minority stress may be adversely affecting physiologic processes. However, there is limited data on cardiovascular health conditions of SM adults and various demographic subgroups (e.g., sexual orientation x race). This makes it difficult to develop health programs to improve health and address disparities in this population. This project will examine disparities by sexual orientation in cardiovascular health conditions. Specifically, the team will: (1) assess disparities in prevalence and incidence according to sexual orientation of selected cardiovascular-related condition (cardiometabolic conditions, cardiovascular disease) and (2) examine and decompose the role of social determinants on cardiovascular health disparities. Further, in a sub-aim, the team will explore the mediating role of telomere length in explaining cardiometabolic health disease disparities by sexual orientation. These aims will be achieved by linkage of survey data from the Kaiser Permanente Research Bank (KPRB) datasets with the Kaiser Permanente electronic health records. The analysis will identify significant disparities and, through decomposition methods, quantify the role of selected social determinants (e.g., education, income, discrimination) in driving these disparities. Results of this work can be used to set health program targets while decomposition results can guide the selection of strategies to address disparities. It also serves as a foundational work for more in-depth epidemiologic, translational, and implementation research on SM disparities.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This proposal seeks to understand how proteins located in the cell membrane work as gatekeepers to selectively allow compounds into or out of the cell. Such gatekeepers are known as or ATP-binding cassette (ABC) transporters, because they use the energy of ATP (adenosine triphosphate) hydrolysis to transport compounds across the cell membrane. Bacterial ABC importers are essential for organism survival, controlling the rate of uptake for nutrients scavenged from the bacterium’s environment. Control of the rate of transport precludes over-accumulation of a nutrient that is beneficial at low concentrations but is potentially toxic at high concentrations. While a subset of ABC proteins contains an additional “accessory” domain that can regulate the uptake of compounds by shutting off the transporter, it is unclear why certain transporters contain these domains while others do not. However, we do understand that certain transporters are “turned off” when a specific compound or protein binds to this accessory domain. Other accessory domains regulate by “sensing” changes in the microenvironment and reacting accordingly. To decipher this mechanism of regulation, the PI’s laboratory combines biochemical and biophysical experiments with structural biology to understand how both the overall architecture and transport mechanism restricts or allows nutrients to enter the cell. This research program will define the molecular mechanism that controls nutrient uptake and allow researchers to understand how multiple transport systems work in concert within an organism to maintain cell survival. With a focus on a broad range of ABC transporters that recognize diverse substrates and fit into the two classes (Type I/Type II), we will continue to examine how topology and selectivity are the driving forces in virulence. This research program has set out to close critical gaps in the understanding of the fundamentals of the transport mechanism present in all bacteria. The results will yield insights into how regulatory domains modulate transport across all organisms, crucial for cell v iability .

NIH Research Projects · FY 2025 · 2025-09

Abstract Infants and children with congenital heart defects (CHD), inherited arrhythmia syndromes, and congenital disorders of cardiac conduction often require cardiac implantable electronic devices (CIEDs). Some infants receive a CIED within hours, or even minutes, of birth. Since intravenous access to heart in young patients is limited by the small vein size, the optimal approach to affixing a CIED to the heart of such patients is to open the chest and sew the cardiac lead directly to the myocardium (“epicardial leads”) as opposed to passing it through veins and affix to the inside of the heart (“endocardial leads”). Unfortunately, once epicardial leads have been implanted, the patient is no longer eligible to receive magnetic resonance imaging (MRI) exams. This is because electric fields produced by the MRI machine can interact with implanted leads, causing excessive tissue heating and potential thermal injuries. MR-conditional CIEDs with endocardial leads have been approved by the FDA, but no equivalent system exists for children with epicardial leads. This leaves the most vulnerable patient population unable to receive the standard of care that they need the most, as children with heart disease often require complex clinical decision making which highly benefits from MRI’s sensitivity and accuracy. The problem is exacerbated by the fact that there is no straightforward method to extract epicardial leads, so children who receive these leads are excluded from benefits of MRI for life, even if an FDA-approved endocardial system is later placed when they are older. This forces clinicians to resort to CT and X-ray imaging, which not only produce sub-optimal images but also expose the young children to significant doses of ionizing radiation, increasing their lifetime risk of cancer. Our long-term goal is to make MRI technology fully accessible to children with CIEDs. Here we propose to test the hypothesis that vertical MRI scanners with a 90° rotated RF field orientation generate substantially less RF heating around leads of epicardial CIEDs with realistic and clinically relevant configurations. Our hypothesis is based on our simulation studies (unpublished) of a commercially available vertical MRI coil (Oasis, Fujifilm), which generated a 700% less local specific absorption rate (SAR) of energy deposition at the tips of epicardial leads in a pediatric patient model compared to the status-quo quadrature birdcage body coil. At present, there is highly limited literature available on CIED SAR specifically for vertical MRI scanners. We will develop a virtual family of pediatric patient models with trajectories of both epicardial and endocardial leads. We will also develop and experimentally validate ISO/TS 10974 standard compliant active implantable medical device (AIMD) model of the implants based on transfer function methods and use the model to predict RF heating during MRI in 1.2 T vertical systems (unlabeled) and compare to RF heating of endocardial CIEDs in horizontal systems at 1.5 T (labeled). Based on the results, we will develop lookup tables to select imaging parameters that constrain RF heating to clinically safe levels.

NIH Research Projects · FY 2025 · 2025-09

The 2025 Epigenetics Society Conference, "DNA, RNA, and Chromatin Epigenetics: Disease and Development," will take place October 15-17, 2025, at Northwestern University’s Simpson Querrey Biomedical Research Complex (SQBRC). The meeting will advance understanding of epigenetic mechanisms and their roles in health and disease, addressing key questions at the interface of basic and translational research. Approximately 200 attendees, including leading scientists, early-career researchers, and trainees, will present and discuss cutting-edge findings and methodologies. The program features research presentations, interactive poster sessions, and discussions of technologies including single-cell sequencing, spatial transcriptomics, and machine learning. Topic areas include therapeutic targeting of epigenetic mechanisms, RNA modifications, and environmental influences on epigenetic regulation. The conference will also strengthen mentorship, professional development, and collaboration to accelerate scientific progress. New initiatives, including a Visionary Network mentoring forum, will focus on career planning, grantsmanship, publishing strategies, research rigor and reproducibility, responsible conduct of research, project/lab management, conflict resolution, and effective scientific communication. Travel awards and registration waivers will be provided based on scientific merit and programmatic relevance, and abstract quality. Plenary and themed sessions will highlight seminal advances and emerging tools across the field. Aligned with the NIH mission, this conference will drive biomedical research progress, inform therapeutic strategies, and strengthen translational applications in epigenetics, shaping future research directions and improving health outcomes for individuals affected by epigenetically influenced diseases.

NIH Research Projects · FY 2025 · 2025-09

The goal of this proposal is to define the optimal interval for women to delay pregnancy after discontinuing long-acting, high-potency glucagon-like peptide-1 receptor agonists (GLP-1 RAs). While GLP-1 RAs are now established therapies for the prevention and management of cardiovascular disease in those with overweight, obesity, or diabetes outside of pregnancy, the impact of the timing of GLP-1 RA discontinuation on pregnancy, postpartum, and offspring outcomes is uncertain. This is critical to understand for several reasons. First, a majority of the >15 million adults currently using GLP-1 RAs are reproductive-aged women with another >30 million are eligible for treatment. Second, trial data in adults demonstrate rapid weight regain and worsening of cardiovascular health (CVH) parameters such as blood pressure and glycemic status following discontinuation of GLP-1 RAs whereby nearly all the CVH benefit from the therapy is lost. Third, worsening CVH in pregnancy, independent of baseline CVH, is associated with worse maternal and offspring outcomes. Therefore, the rapid weight regain and declining CVH expected when GLP-1 RAs are discontinued proximate to the beginning of pregnancy may be concentrated during a critical window for maternal and offspring health and lead to unintended short- and long-term harm with regards to pregnancy, postpartum, and offspring outcomes. Yet, a pre-pregnancy randomized trial of GLP-1 RA discontinuation is not feasible: it would require >10,000 women to be randomized to strategies that require prolonged delays in attempting pregnancy, and thus it is unlikely ever to be performed. There is, thus, a pressing need for high-quality observational data to rigorously and efficiently address this critical evidence gap and inform clinical guidelines and clinician-patient discussions. Therefore, our highly experienced multi-disciplinary team proposes an innovative application of the target trial framework to definitively answer this clinically relevant question. We will combine state-of-the-science methodologic approaches with a large, diverse, real-world dataset that contains granular data on >280,000 reproductive-aged women with repeated clinical and laboratory values, prescription fills, and linked mother-child records. We will conduct two target trials to examine the effect of varying intervals of delaying pregnancy after GLP-1 RA discontinuation in the two key populations eligible for GLP-1 RAs: (1) those with diabetes and (2) those with overweight or obesity but without diabetes. We will specifically examine the effect of delaying pregnancy after GLP-1 RA discontinuation on maternal cardiovascular outcomes in pregnancy (Aim 1) and the postpartum (Aim 2) and offspring CVH predictive of long-term cardiovascular disease risk (Aim 3). We will also use machine learning methods (e.g., SuperLearner models) to enhance the rigor of our study. Completion of these aims will yield novel and significant insights into the optimal timing of pregnancy after discontinuation of GLP-1 RAs to optimize intergenerational CVH.

NIH Research Projects · FY 2025 · 2025-09

Selenium deficiency is common in ulcerative colitis (UC), even during periods of quiescent disease, and deficiency of selenium in UC is associated with an increased risk for disease flares and need for colectomy. Recent evidence demonstrates that coloncytes can directly uptake selenium and use it to synthesize selenoprotein-P (SELENOP), which is secreted basolaterally into the colonic microenvironment. Myeloid specific loss of SELENOP, but not epithelial specific loss of SELENOP, results in increased susceptibility to induction of colitis. Through large integrated human single-cell and spatial transcriptomics datasets, we observed an inverse association between myeloid SELENOP expression and disease activity in UC. In a prospectively recruited cohort of biologic treated moderate-severe UC patients, non-responders to IL23 blockade had significantly lower myeloid SELENOP expression and increased myeloid ferroptosis. These myeloid transcriptional changes for SELENOP and ferroptosis were not seen for non-responders to anti-TNF or anti-trafficking therapy. In-vitro data confirmed effects of selenium exposure for increasing anti-ferroptosis pathways in myeloid cells. Trace element profiling of human tissue and blood confirmed selenium deficiency in active UC patients in colonic tissue biopsies, but not blood, demonstrating a need for colonic microenvironmental selenium supplementation. A small prior placebo-controlled clinical trial in mild-moderate UC demonstrated improved symptom activity with selenium supplementation, but proof-of-concept data is lacking in moderate-severe UC. We aim to complete a proof-of- concept clinical trial for selenium supplementation in moderate-severe UC patients starting advanced biologic or small molecule therapy. Using human biospecimens from this trial, we aim to develop an exposure-response model for selenium and study changes in myeloid ferroptosis with selenium supplementation in UC. The data generated from this proposal will be used to design and power a larger multi-center clinical trial to confirm clinical effects of selenium supplementation in moderate-severe UC and establish whether this clinical effect is greater for patients being treated with anti-IL23 biologics.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Regulatory T cells (Tregs) are a subset of CD4+ T cells that maintain immune self-tolerance and mediate the resolution of lung injury during viral pneumonia by suppressing overexuberant inflammatory responses and facilitating tissue protection and repair. During viral infection, the lung microenvironment imposes substantial metabolic stress on Tregs. Tregs depend on mitochondrial oxidative phosphorylation, a process driven by fatty acid metabolism, to optimally exert their function. While there is evidence that Tregs have the potential to be clinically efficacious as a cellular therapy for patients with severe viral pneumonia, there is a need to ascertain the context-specific metabolic mechanisms that promote Treg function to enhance their therapeutic activity. Carnitine palmitoyltransferase I A (CPT1A), the rate-limiting enzyme in long chain fatty acid (LCFA) oxidation, imports LCFAs into the mitochondria where they are oxidized to acetyl-CoA to enter the tricarboxylic acid (TCA) cycle to drive oxidative phosphorylation. While established in the extreme microenvironment of tumors, it is unknown whether Tregs depend on LCFAs for their function during viral pneumonia and whether short chain fatty acids (SCFAs), which fuel oxidative phosphorylation by providing acetyl-CoA for TCA use, are able to sustain Treg function in LCFA-limited contexts. In preliminary experiments, we bred mice with Treg specific deletion of CPT1A (TregCPT1AKO) and challenged them intratracheally with influenza A and subcutaneously with B16F10 melanoma tumors. While TregCPT1AKO mice exhibit no signs of autoimmunity at homeostasis, they are more susceptible to mortality from severe influenza pneumonia and exhibit slower tumor progression compared with controls. These results suggest that CPT1A is dispensable to maintain homeostatic self-tolerance but is necessary for Treg function during pathologically-induced microenvironmental mitochondrial stress. Therefore, we hypothesize that Tregs require CPT1A-mediated mitochondrial LCFA metabolism to provide lung tissue protection following severe viral pneumonia. We will causally test this hypothesis by studying mice with Treg-specific deletion of CPT1A in the influenza A mouse model of viral pneumonia. Our Specific Aims are 1) to determine whether CPT1A-mediated long chain fatty acid oxidation is necessary for Treg tissue-protective function during influenza A virus pneumonia and 2) to determine whether long chain fatty acids enter the mitochondrial TCA cycle and whether short chain fatty acids are sufficient to maintain acetyl-CoA levels in and function of LCFAO-deficient lung Tregs during influenza A pneumonia. The PI will benefit from the collective intellectual and technical expertise of their mentorship committee—comprised of experts in immunology, metabolism, epigenetics, and lung disease—who will provide him with project support and mentorship throughout the funding period. The resource-rich environment afforded to the PI is equipped with all necessary facilities, equipment, and expertise to complete the research strategy and training plan.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Pseudomonas aeruginosa (Pa), a ubiquitous, environmental Gram-negative bacterium, is a leading cause of healthcare-associated infections worldwide resulting in >400,000 deaths annually. Treatment is challenging because Pa harbors a wide array of intrinsic and acquired antibiotic resistance mechanisms. Of all invasive infection types, Pa bloodstream infections (PABSI) have very poor patient outcomes and bloodstream infections secondary to Pa are more lethal than those of any other bacterium. The reasons for this are unclear. Recently, we were the first to show that during bloodstream infection, Pa traffics to the liver, expands in the gallbladder, and is excreted in the gastrointestinal (GI) tract. Additionally, we showed that the gallbladder was the critical organ that facilitated high level Pa excretion and promoted transmission. To survive in the liver and gallbladder and establish a niche in the GI tract, Pa must be adapted to thrive in bile, a complex fluid produced by the liver, concentrated in the gallbladder and excreted into the GI tract. Bile is composed of bile acids and salts, cholesterol, proteins, and lipids that are inherently antimicrobial. Resisting bile exposure is universally critical for pathogen success in the GI tract and the GI-resident bacterial population serves as a reservoir for invasive Pa infections. To dissect the mechanisms by which Pa resists bile exposure, this project will explore an exciting, newly identified bile resistance sodium-hydrogen antiporter, and, by expanding our bile resistance analysis of multiple Pa strains, identify shared (common) and strain-specific bile resistance pathways. The approach of Aim 1 is two-fold. First, we will investigate the role of the sodium-hydrogen antiporter, shaA-F, in bile resistance. This operon was identified by an early comparative transposon-insertion (INSeq) experiment as critical for bile resistance. Additionally, we will characterize the role of each protein in the sha operon in GI carriage and pathogenesis. Second, to complement genetic approaches, RNA sequencing will be utilized to profile global bacterial transcriptional responses to bile, with an emphasis on understanding if and how sha is regulated by bile exposure. Aim 2 will deploy comparative transposon insertion sequencing (INSeq) across additional representative Pa strains to identify additional shared and strain-specific genes necessary for bile resistance. Following gene deletion, both shared and strain-specific targets will be assayed in vitro and in vivo to determine their impact on bile resistance and Pa pathogenesis in a model of PABSI. The proposed work will produce the first multi-strain comparative analysis of Pa responses to bile exposure by deploying a powerful combination of genetic and transcriptomic approaches. As bile resistance is critical for the establishment of pathogens in the human GI tract and bile exposure increases antimicrobial resistance in many pathogens, we believe that pathways identified by this proposal present exciting new targets for the development of antimicrobial agents to treat Pa infections.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Stressful events, overeating, and obesity have been associated with cardiovascular disease (CVD). Characterizing the relationship between these factors may inform targeted and timely interventions to prevent overeating episodes. To date most research relies on self-reports to identify stress and overeating episodes. Subjective self-reports are often retrospective and do not capture continuous physiological patterns to enable automated predictors of overeating. There is a need for objective approaches that continuously measure stress and overeating in real-time to further advance understanding of stress patterns that contribute to overeating. Wearable devices have become a powerful source for collecting health-related data using embedded sensors. Significant advances in technology have been made, including use of machine learning algorithms that process wearable data in real time. However, it is unclear how these real time indicators advance our understanding of the relationship between stress, overeating, and obesity status. Moreover, most wearable devices collect sensor data in real time and process the data offline post hoc. We have developed a Band-Aid-like flexible wearable that can collect electrocardiography, photoplethysmography, and skin temperature data and an infrared (IR)-enabled camera that can collect both IR and color images. Building upon our preliminary research, the device can detect 1) stress using the Band-Aid-like device’s data and 2) eating using the IR- enabled camera’s data among a general population in free-living conditions. Data from these devices will then be used to build reliable and resilient (i.e., adaptive to the individual over time) machine-learned models that run in real time. Deploying machine learning algorithms with these novel features will likely improve stand- alone devices that can detect stress or overeating in real time, making them a viable option for timely intervention compared to existing wearable devices that simply collect sensor data for offline analysis. The aims of this study are to refine and deploy machine learning algorithms to detect stress (on a Band-Aid- like device) and overeating (on an IR-enabled camera) in real time. We will first assess the robustness of the stress detection model and refine the machine learning algorithms in a controlled setting where we can induce stress. Next, we will test the performance of these algorithms in real-world settings. We will then use this information to identify patterns of stress that can predict overeating. As an exploratory aim, we will determine if dynamically changing and personalizing the models to each individual improves model performance. This project has far reaching implications as it will further understanding of patterns in stress and overeating, and their relationship, to help predict overeating - thus providing fundamental knowledge about how we can deliver timely behavioral interventions to reduce CVD risk.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Exposure to toxic compounds whether due to industrial accidents or mass casualty events involve contact with multiple tissue surface and organs that are detrimental to human health. A chemical compound will have varied acute and latent effects dependent on contact with the cornea, upper airways, or the skin. Exposure to nerve agents and opioids can produce a broad range of clinical manifestations, long term CNS damage, and death. Mere decontamination is not adequate for preserving human health in these exposures. Developing a comprehensive understanding of specific ‘perturbagens’ and their toxidrome effect will allow scientists to better develop first-line therapies to address acute and late complications which may have broad applications to related toxic agents. Medical countermeasures are effective when they can be rapidly and easily administered in a limited treatment window to large numbers of people and therefore requires a thoughtful integration of biology, chemistry, drug development, clinical medicine, and response coordination. The aim of this proposal is to seek funds to bring together leading scientists in toxicology with experts in drug development, countermeasures biology, and new investigators in related fields. The conference on ‘Innovations in Countermeasures and Toxicology Research’ has 11 planned scientific sessions to address several emerging topics in the biology of toxic chemical exposures as well as challenges for therapeutics development. The morning keynote sessions will be comprised of three 25-minute main talks followed by Q&A from experts in drug delivery, immunomodulation, non-invasive sensor technology, translation to industry, and clinical trials. Morning sessions are comprised of 5 plenary short-talks to the general audience across all disciplines selected based on abstracts scores, designed to foster cross-fertilization of research methodologies and a better understanding of related pathobiology mechanisms. The afternoon sessions will consist of dual concurrent symposia involving (1) exposure to epithelia (skin, eyes, and lungs) (2) exposure to neurological agents and ultra-potent synthetic opioid agents. To create networking opportunities a session is dedicated to fifteen 5-minute short-talks to the general audience given by trainees. The non-intimidating setting is an invitation to “come see my poster” for a robust poster session that follows. A noon workshop is planned for the entire audience on ‘Interprofessional Collaboration and Team Science’ lead by a renowned scientist in organizational behavior. To-date we have confirmed a group of 6 speakers, 7 abstract reviewer from academia and government. Speakers and symposium chairs are requested to stay for the entire meeting to encourage lively discussion throughout the conference. We will leverage our partner societies to attract new investigators to attend the conference. Early stage investigators and trainees will be a supported through our fundraising efforts to support meeting scholarships. We believe that our conference plans will be a means to attract scientists from related fields and for young scientists to meet and to ultimately enhance the Chemical Countermeasures Research Program (CCRP).

NIH Research Projects · FY 2025 · 2025-09

Project Summary: The increased risk of metabolic disorders in individuals subjected to shiftwork and those experiencing sleep loss indicate that disruption of day/night behavioral rhythms represents an emerging factor in the linked epidemics of obesity and diabetes. In mice, consumption of a high fat diet (HFD) leads to increased feeding during the light period (the normal sleep phase) and disrupted circadian and metabolic rhythms. Conversely, nighttime-restricted feeding (the normal active phase) has emerged as a dietary strategy to combat obesity and diabetes. We have recently shown that time-restricted feeding (TRF) with HFD provided only during dark period mitigates obesity due to increased metabolism of food to produce heat. We have further shown that the molecular clock controls the synthesis of creatine within adipocytes, fueling a futile cycle of ATP consumption which is required for the metabolic benefits of nighttime-restricted feeding. However, we have not yet identified the brain signals that promote increased diet-induced thermogenesis during nighttime-restricted feeding, nor the epigenetic mechanisms at the level of the adipocyte that are required for circadian control of futile creatine cycling in response to time-restricted feeding. Here we propose to exploit integrative neurogenetic and circuit-based approaches in combination with behavioral, bioenergetic, metabolomic, and genomic strategies to examine the interorgan mechanisms by which the brain-adipose axis drives the health benefits of TRF. Aim 1 will test the hypothesis that the circadian SCNAVPàDMH neurocircuit drives energy expenditure rhythms to maximize health with nighttime-restricted feeding. This aim builds upon our finding that AVP cells within the SCN project to DMH neurons which are important in regulation of energy expenditure and thermogenesis. We will examine the effect of time-restricted feeding on energy expenditure and thermogenesis following (a) chemogenetic manipulation of the activity of DMH-projecting AVP neurons and (b) after genetic manipulation of molecular clock activity within these cells. These studies will identify specific cells mediating communication between the SCN and the DMH that determine the metabolic benefits of nighttime-restricted feeding. Aim 2 will test the hypothesis that the adipocyte circadian clock synchronizes thermogenic rhythms with the light cycle through the epigenetic control of creatine synthesis. We will determine how the brain clock aligns adipocyte circadian cycles with the light-dark cycle through autonomic stimulation of adipose thermogenesis, and we will elucidate the epigenetic mechanisms that link clock transcription cycles to rhythms of creatine synthesis. Collectively, these studies will define the mechanisms through which the brain-adipose axis integrates environmental and intrinsic circadian signals underlying the healthful response to time-restricted feeding.

NIH Research Projects · FY 2025 · 2025-09

Neutrophil activity in tissues can exacerbate inflammation and promote tissue damage, as seen in inflammatory bowel diseases (IBD). Thus, studies focused on PMN trafficking are of continued interest and physiological significance. Crossing of the endothelial cell (EC) barrier is the first critical regulatory step in tissue PMN effector function and targeting existing and novel signaling molecules/pathways involved in this process is an attractive therapeutic strategy. miRNAs-focused therapies are an exciting emerging field, with several miRNA therapeutics already approved for clinical use and more being tested in clinical trials. Identification of miRNAs has been acknowledged by the 2024 Nobel Prize in Medicine, highlighting their significant impact and potential as therapeutics. As such miRNAs present an exciting opportunity for therapies, as their expression can be easily manipulated using synthetic miRNA mimics or antagonists, which can be synthesized as cell permeable molecules with superior tissue uptake. miRNAs broadly regulate many biological processes and have been implicated in IBD pathogenesis and heightened immune response. Specifically, miRNAs can regulate organization of the actin cytoskeleton, cell polarity, cytokine/chemokine signaling and cell adhesion, all of which are critical regulatory process of neutrophil transendothelial migration (TEM).Thus, in the current studies we propose to perform an unbiased miRNA profiling in circulating PMNs in clinically relevant infectious, salmonella- induced and DSS-induced colitis/injury models followed by phenotypical and functional target validation with the goal of 1. Identifying novel microRNAs that regulate PMN TEM in gut inflammation and 2. Establishing whether manipulating miRNA activity can effectively suppress PMN TEM and improve resolution of gut inflammation. In preliminary work we established the premise for targeting reduction in neutrophil migration and tissue accumulation to improve disease outcomes in these models. We also optimized all relevant protocols for blood neutrophil isolation and mRNA sequencing. These high-risk-high-reward studies are well suited for the R21 funding mechanism as they provide a platform for the development of novel interventions, such as miRNA therapeutics, aimed at regulation of PMN crossing of the vascular wall and trafficking into tissue, which will help achieve important clinical endpoints, including resolution of mucosal inflammation and wound healing.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Despite having numerous effective HIV interventions and making considerable gains in HIV prevention and care objectives, progress is lagging to meet Ending the HIV Epidemic (EHE) initiative goals by 2030, especially among individuals disproportionately impacted by HIV. Dissemination and implementation science (D&IS) is recognized as a critical component to EHE to inform the effective scale out of HIV interventions. In recent years, there has been a substantial increase in D&I-related studies, facilitated in great part by federal agencies’ commitment to fund academic–community D&I research projects and D&IS support through the NIH Centers for AIDS Research and NIMH AIDS Research Centers. The Implementation Science Coordination Initiative (ISCI) at the Third Coast Center for AIDS Research has been funded by NIH EHE to provide coordination and D&I scientific leadership to EHE research projects over the last 5 years, during which we have synthesized HIV- specific D&I knowledge; established systems for collecting, analyzing, and reporting D&I data from EHE projects; and created tools to disseminate D&I resources and research findings to EHE-related researchers, practitioners, and policymakers. Under this application for a Coordination, Consultation, and Data Management Center, we intend to expand our activities as a national resource and continue collaboration with the Regional Consultation Hubs (RCHs) through three aims: (1) INTEGRATE implementation and effectiveness data across NIH EHE- funded projects to create generalizable knowledge. We will use shared decision-making with projects to choose measures and common data elements for determinants, strategies, and outcomes that will go into a harmonized measures library; deploy a data coordination infrastructure to collect high-quality project data; and identify opportunities for integrated or meta-analyses. (2) ADVANCE the field of D&IS in HIV by facilitating knowledge sharing of D&IS methods and conducting tailored D&IS trainings. In collaboration with the RCHs, EHE researchers, and local/national implementation partners, we will convene expert panels to focus on key science- to-practice gaps that D&IS can help close; conduct timely systematic and scoping reviews to guide the field toward promising implementation strategies; support professional development for early-stage investigators and workshops tailored implementation practitioners; and provide scientific leadership and technical assistance on D&IS methods and protocol development. (3) DIFFUSE D&I research methods and findings to varied research, practice, and policymaker audiences to accelerate translation from research to practice. We will maintain our popular website and newsletter that spotlight findings from EHE projects, share trainings and funding opportunities, and host our open-access Literature Review and EHE Project dashboards; create multimedia implementation packages and policy briefs for “best practice” implementation strategies; disseminate EHE projects findings in symposia at HIV and D&IS conferences; and edit two special journal issues that showcase findings from EHE projects, with an emphasis on cross-project lessons learned.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Despite the remarkable success of antiretroviral therapy (ART) to control HIV-1 infection, viral reservoirs persist indefinitely under treatment. These remaining viral populations constitute the principal burden for an effective HIV-1 cure, as they lead to a rapid “rebound” in viremia when treatment fails or is discontinued. Viral reservoirs in ART treated individuals are constituted by latently infected long-lived immune cells. Additionally, the reservoir comprises populations that produce low levels of viremia even in presence of high levels of ART. The sources of this residual viremia might play a key role in the fast “viral rebound” often observed after therapy cessation. Different studies demonstrate that the reservoirs are rapidly established early after infection and distributed throughout the body in multiple anatomical sites. In addition to T-CD4+ cells, a growing number of studies suggest that other T-cells and myeloid cells such as macrophages and mast cells constitute potential active and/or inducible reservoirs too. This capacity to establish reservoirs in a wide variety of cellular targets and anatomical compartments is promoted by HIV-1 accessory and regulatory proteins and might lead to viral characteristics directly associated with the producer cell type. In this proposal, we aim to characterize viruses produced by different cell types and their corresponding integrated provirus using tissue “ex vivo” infections. Furthermore, we will study the sources and characteristics of the viral particles that comprise the residual viremia from various anatomical compartments using clinical samples from people living with HIV-1 under ART. We will use our newly developed pipeline that combines viral immuno-capture (v-IC) from multiple cell types, with proviral sequencing in the same cell types, long-read deep viral sequencing, and viral particle multi-omics. This new pipeline will be very relevant for HIV-1 cure studies to identify the sources of viremia during ART and to better analyze the viral reservoirs.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY A key driver of the obesity epidemic is the excessive consumption of highly palatable, calorie-rich foods. Obesity, in turn, leads to substantial alterations in taste sensitivity and food preferences, perpetuating the obese state. However, the neurobiological underpinnings of the interaction between obesity and taste sensation remain largely uncharted. The overall objective of this application is to determine how the brainstem neurons that convey taste information are impacted by obesity. To achieve this, we propose studies to identify obesity-dependent changes to taste neurons at the circuit-, cellular- and molecular-level. In the long-term, we envision that these studies will reveal platforms for therapeutic intervention aimed at disrupting the self-perpetuating cycle of overconsumption in obesity.

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 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 2026 · 2025-09

There are 24,000 stillbirths annually in the United States. In population-level studies, unexplained stillbirths are 30-40%. However, in medical-center based studies with more detailed work-up, the rate is <10%. These studies consistently show that placental histopathology is the most informative datum. This may seem counterintuitive – unlike whole exome sequencing or hemoglobin F flow cytometry, histopathology is widely available. The limitation is the sparsity of human experts. There are around 100 expert perinatal pathologists in the United States, almost all in urban academic medical centers. The situation is unlikely to improve – most projections show the total number of pathologists going down. Our solution is to develop machine learning (ML) models that can make the key placental histopathologic diagnoses in stillbirth. Placental findings may reinforce the significance of information already known, such as evidence of maternal vascular injury in patients with hypertensive disorders of pregnancy. Alternatively, placental findings may be critical, but have no established way of diagnosing them before delivery, such as histiocytic intervillositis. We will test these models in a group of >1500 pregnancies that ended in stillbirth. We will perform detailed abstraction of clinical, obstetric, and laboratory information. Pathologists and maternal-fetal medicine experts will confer on classifying the cause of demise. We will test the importance of placental diagnoses in identifying the anomaly leading to demise and evaluate whether machine learning diagnoses give meaningful information on the causes of demise. To improve generalizability, we will test our model using a set of 500 stillbirths from the Mayo Clinic. Better identifying the cause of demise has immediate and long-term benefits. Understanding what happened is an important part of grieving for patients and families experiencing stillbirth. The benefits are magnified if patients attempt a subsequent pregnancy, since their risk can be better delineated. Knowing the cause of a prior stillbirth can allow personalized treatment. Researchers focusing on specific causes of stillbirth need to identify patients at risk of that cause and to target them for treatment. In the US, stillbirths are reviewed in multidisciplinary conferences. The models developed in this study can improve the work of pathologists in these conferences and, potentially, support decision making in these groups. With sufficient improvement, these models can be piloted in lower-resource settings as full replacement for pathologists or conferences.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Glaucoma care requires treatments that are safe, efficacious, and predictable. Glaucomatous optic neuropathy is a leading cause of irreversible blindness worldwide, and so far, no direct optic nerve treatment can reverse glaucoma. Thus, glaucoma treatment is risk factor modification. The only modifiable risk factor is elevated intraocular pressure (IOP). IOP reduction has been proven to mitigate glaucoma progression. Yet current medical and surgical methods often fail to provide long-term IOP reduction to prevent blindness. Researchers attribute this to a lack of a comprehensive understanding of pathologic IOP in glaucoma. To reduce IOP, drugs (such as muscarinic agonists, rho-kinase inhibitors, or nitric-oxide donors) and Minimally Invasive Glaucoma Surgeries (MIGSs) target the trabecular meshwork (TM) to decrease aqueous humor outflow (AHO) resistance. Unfortunately, pathological AHO resistance in glaucoma is progressive, and medications become less effective over time, leading to patients becoming medically non-responsive. In addition, patient compliance remains a key limitation for medications, eventually leading to surgical interventions. MIGS are a quick and safe alternative to lower IOP by surgically ablating or bypassing pathological TM. However, in large-scale, well-controlled clinical trials, average MIGS efficacy was lacking, providing only few mmHg of total IOP reduction. Therefore, improving MIGS efficacy remains a unmet clinical need. We argue that the lack of trabecular MIGS efficacy is caused by a poor understanding of the circumferential AHO anatomy and pathophysiology, which leads to a lack of surgical planning. Clinically, focal trabecular bypass and ablation in glaucoma patients near-universally target the TM in the nasal iridocorneal angle; there is no tools available for surgeons to tailor MIGS to suit individual patient’s needs. We will develop a robotic anterior-segment optical coherence (AS-OCT) to visualize the circumferential AHO pathways and create the digital twin of the AHO pathway anatomy. Using the digital twin, we will further develop an eye-specific hydrodynamic model to predict IOP reduction under different MIGS plans. The robotic AS-OCT will enable researchers to visualize the entire AHO pathways for the first time. The AHO pathway’s in vivo circumferential anatomic features, including segmental Schlemm's canal size distribution, the total number of collector channels and their circumferential distribution, have not been accessible to researchers before. The concept of a digital twin of the eye is principally new, providing new ways to visualize and track ocular anatomical alterations and allowing ophthalmologists to perform surgical planning for the first time. Finally, integrating the hydrodynamic model with the digital twin allows for predicting the effects of different MIGS plans to achieve optimal patient outcomes, leading to personalized, precision glaucoma care. We will also deposit the hydrodynamic model at our GitHub website to ensure broad dissemination to the research community.