Northwestern University

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT The Robert H. Lurie Comprehensive Cancer Center (LCC) of Northwestern University, as an NCI-designated Comprehensive Cancer Center, has excelled as a Lead Academic Participating Site (LAPS) within the NCI National Clinical Trials Network (NCTN). LCC aims to build upon its established infrastructure to drive innovation in cancer clinical trials, particularly early-phase and multi-center studies, while prioritizing health and expanding access to populations across our catchment area. Through our robust leadership, strong operational framework, and extensive network of integrated component sites, we strive to deliver high-quality, impactful clinical trials that advance cancer care. By aligning scientific expertise, operational efficiency, and community engagement, the LCC will continue to enhance trial accrual and expand access to cutting-edge treatments for patients. LCC members play pivotal roles in the NCTN through leadership positions and scientific contributions that shape trial design and implementation. Faculty serve as national PIs, protocol chairs, and committee leaders across multiple cooperative groups, including Alliance, ECOG-ACRIN, SWOG, and NRG Oncology. For example, Dr. Al B. Benson III serves as Vice Chair of ECOG-ACRIN, co-chair of the Cancer Care Delivery Research Committee, and chair of several critical protocols. Dr. Daniela Matei leads translational science initiatives for NRG and chairs high-impact protocols in gynecological oncology. LCC investigators are also actively engaged in the development of innovative trials, such as leveraging ctDNA biomarkers in pancreatic cancer, led by Dr. Akhil Chawla through the Alliance cooperative group, and evaluating novel symptom science approaches, spearheaded by Dr. Sheetal Kircher within ECOG-ACRIN. This comprehensive engagement ensures that the LCC is a vital driver of innovation and collaboration within the NCTN. Over the last 5 years, LCC has focused on expanding clinical trials to 14 Network Locations which have been added as integrated components to the LAPS grant. Expansion network locations will significantly enhance the LCC's ability to increase accrual to NCTN trials by bringing clinical research opportunities closer to patients across the catchment area, thereby reducing barriers to participation and promoting access to cutting-edge cancer care. Over 900 patients were accrued to NCTN interventional trials during the past funding period. By aligning scientific expertise, operational efficiency, and community engagement, the LCC will continue to enhance trial accrual and expand access to cutting-edge treatments for patients, improving outcomes and reducing disparities.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) in Parkinson’s disease (PD) occurs over several years. Identifying early mechanisms of this degeneration can aid in developing neuroprotective treatments, as current therapies are given only after significant loss of nigrostriatal function. One common monogenic form of late-onset PD is caused by mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, leading to a hyperactive kinase. LRRK2-medated PD resembles idiopathic PD, showing similar pathological features, including age-dependent loss of DA neurons in the SNc Carriers of LRRK2 mutations are suitable candidates for early therapeutic interventions. However, currently no unifying hypothesis explains how LRRK2 contributes to DA neuron dysfunction. In a genetic mouse model with the common LRRK2 mutation (LRRK2G2019S), we found disruptions in release sites of DA axons and loss of cilia in striatal cholinergic and parvalbumin interneurons (CINs and PVINs, respectively). Therefore, we hypothesize that these cellular phenotypes may be linked through a signaling loop involving the glial cell line–derived neurotrophic factor (GDNF) and neurturin pathways, which support and maintain DA neurons. This study will examine cell-type-specific alterations in LRRK2G2019S mice to investigate how LRRK2 mutation affects this neuroprotective signaling pathway and DA neuron health at early stages of the disease. Aim 1 will investigate LRRK2-mediated disruptions at DA release sites in vulnerable DA neuron subpopulations in PD. It will also assess the age dependency and regional pattern of cilia loss in CINs and PVINs. We propose that impaired release machinery decreases key signaling molecules like sonic hedgehog (Shh) in the nigrostriatal pathway, reducing neurotrophin production by striatal interneurons. Age-related cilia loss exacerbates the issue, further diminishing neurotrophin-induced intracellular signaling. Aim 1 will also define the molecular mechanisms underlying these cellular dysfunctions related to LRRK2 mutations. Aim 2 will investigate how LRRK2-linked cellular disruptions affect key components of neurotrophic signaling and result in decreased DA neuron markers and ultimately DA neuron loss in a dual hit model of PD. To enhance the therapeutic impact of our findings, we will test whether clinically relevant LRRK2 inhibitors can reverse these disruptions and propose novel therapeutic avenues to restore DA neuron health. Our study will use advanced genetic models, molecular tools, and biochemical methods to explore PD pathophysiology, directly linking LRRK2 to DA neuron health. With the clinical development of small molecule LRRK2 kinase inhibitors, our findings will help identify new targets and pathways to slow disease progression.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Glioblastoma, IDH-wildtype (GBM; WHO grade 4), the most malignant primary brain tumor, has well-defined pre-necrotic, necrotic and recurrent growth phases. Transition to the necrotic phase in primary and recurrent states involves a massive restructuring of the tumor microenvironment (TME), in which there is a dramatic increase in tumor- associated macrophages (TAMs) that are polarized to an immunosuppressive state. TAMs emerge from the perivascular niche and aggregate in high density with hypoxic glioma cells within the peri-necrotic niche (PN) with remarkable temporal similarity. We hypothesize that the spatial arrangement of TAMs and glioma cells within the highly hypoxic PN represents a biologic engine that serves as a sustainable source of TAM immunosuppression and is reliant on their synergistic interdependencies. We propose investigations to better understand mechanisms underlying these events using patient- derived, molecularly characterized GBM neurosphere cultures and RCAS-tv-a mouse model that allows study of the evolution of TME events following necrosis in real-time in vivo and with advanced spatial transcriptomics. We focus on specific signaling events within the PN that cause polarization of TAMs and have preliminary data indicating that the hypoxic expression of podoplanin (PDPN) by glioma cells activates CLEC5A on TAMs, causing an immunosuppressive phenotype through Syk/STAT3 signaling. We also suggest that the direct effects of hypoxia and TGFβ1 activate Hippo signaling and PDPN expression within this niche. Pharmacologic inhibition of Syk as a single agent prolongs survival and enhances the presence of CD8+ T cells in the RCAS/tv-a model of GBM. We hypothesize that therapeutic targeting of CLEC5A signaling by using Syk inhibitors in addition to standard of care chemoradiation, with or without checkpoint inhibitors, will diminish immunosuppression, enhance immunity and prolong survival in preclinical models of primary and recurrent GBM.

NIH Research Projects · FY 2026 · 2026-04

Title: Role of mRNA internal 2′-O methylation in post-transcriptional regulation Project Summary/Abstract: Emerging evidence has proved the pivotal roles of RNA modifications in the control of various fundamental bioprocesses as well as diseases. As a prevalent modification type in most RNA species, 2′-O methylation (Nm) could present at all four ribonucleosides to affect RNA structure, stability, and interactions. In sharp contrast to the extensively studied rRNA Nm and 5′-cap mRNA Nm, Nm occurred at mRNA internal sites were only reported until recently, while its biological functions and underlying mechanisms remain underexplored. By combining Nanopore direct RNA-seq (Nanopore-seq) with our newly developed machine learning method, we recently identified thousands of novel mRNA Nm sites in human cells at single-base resolution and characterized fibrillarin (FBL) as a major 2′-O methyltransferase (MTase) to install this modification. Despite these advances, little is known about the regulatory network by which Nm governs mRNA functions and metabolism, and how Nm is manipulated to ensure the precise and synchronous regulation of gene expression. In our current studies, we propose three independent yet complementary projects to resolve this knowledge gap. By utilizing comprehensive proteomic, molecular, and multi-omics approaches, the first project will identify HNRNPF/H1 as distinct Nm downstream effector proteins and elucidate how this Nm&effector signaling remodels the splicing outcome of Nm-modified mRNAs globally. In addition, our Nanopore-seq results have revealed the evident co-occurrence of Nm with N6-methyladenosine (m6A), the most abundant RNA modifications in mammalian cells. Therefore, our second project will uncover the mechanism underlying the crosstalk between Nm and m6A modification and elucidate the impact of Nm&m6A dual methylation on mRNA fate. Dysregulation of Nm is frequently linked to multiple neurodevelopmental disorders. Hence, our last project will dedicate to discover the functional relevance of mRNA Nm on pluripotency maintenance and neuronal fate decision. Overall, our studies will gain novel insights into the biological functions of mRNA internal Nm and pioneer the Nm-targeting technological innovations to benefit human health.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Mechanistic understanding of living things requires our understanding of how proteins and DNA interact together to generate functional chromosomes. The structure and dynamics of chromosomes ultimately controls all functions of cells, and in turn, multicellular organisms, including humans. Understanding chromosome structure and dynamics and the underlying biochemical interactions defining them are central to preserving human health, dealing with genetic disorders, and fighting pathogenic organisms. Dramatic reorganizations of chromosomes occur throughout the cell cycle: in humans, hundred-million-base-pair long DNAs are genetically deactivated and refolded into the metaphase form to facilitate mitosis, following which are reorganized into cell nuclei harboring once again active gene expression. My laboratory studies chromosome structure and dynamics using a novel combination of cell- and molecule-scale mechanics with state-of-the-art genetic, biochemical, single-molecule and mathematical modeling tools. Chromosome mechanics at the nanonewton scale are central to cell division due to large mitotic spindle forces, and the well-defined elasticity of chromosomes also provides a quantitative readout of internal structural changes. Those micron-scale dynamic reorganizations of chromosomes are controlled by piconewton forces and nanometer steps generated by individual protein machines. Direct mechanistic analysis of chromosome organizational principles and their relation to underlying molecular interactions will transform our understanding of how cells interpret, fold and change their genomes. In turn this will advance understanding of pathologies where those functions are impaired including genetic disorders and cancers and will improve our understanding of how to target those functions in pathogenic organisms. Over the next five years my laboratory will analyze roles Structure of Maintenance of Chromosomes protein complexes (SMCs: condensin, cohesin and SMC5/6 in eukaryotes) and other key genome-acting proteins in organizing chromosomes across the three kingdoms of life, using single- molecule mechanics approaches to directly observe their function. In parallel we will use chromosome and nuclear mechanics studies to study their roles in organizing chromatin at the larger scales of metaphase chromosomes and cell nuclei. The remarkable stability of DNA-protein complexes will be studied using single- molecule and cell-level experiments on “facilitated dissociation” (FD), preliminary studies for which indicate that pathways for spontaneous dissociation – the backbone of our understanding of biochemical interactions – may be kinetically irrelevant compared to competitive binding pathways. This promises a complete revision of how we think about binding affinity in the crowded, competing in vivo environment, replacing the concept of a ligand-receptor affinity with a large competition kinetic matrix, with transformative implications for how we think about regulation of biochemical interaction networks in vivo. Experimental results will be linked to mathematical models and coarse-grained computer simulations of molecular function and genome/chromosome folding.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Currently, many genome-wide association studies (GWAS) show that single nucleotide polymorphisms (SNPs) associated with drug response and drug metabolism are in non-coding regions of the genome, requiring multi- omic data to better ascertain function. Multi-omic data exist for populations of European ancestry and have been used extensively to elucidate the target genes of associated SNPs through studies of expression quantitative trait loci (eQTLs). However, population diversity within publicly available multi-omic databases is sorely lacking, limiting the ability to utilize the greater diversity in African Ancestry populations to enable discovery for all populations. Our work will fill this gap. We plan to 1) Identify regulatory variants affecting drug-metabolizing enzymes using multi-omics data gathered in hepatocytes, 2) Determine the function of eQTLs via a massively parallel reporter assay in HepG2 and 3) Investigate the effect of eQTLs on the enzyme activity of drug- metabolizing enzymes via prime editing. The need for more predictive biomarkers is clear, and our work will fill this gap.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Liver cirrhosis affects 2-7 million adults in the US, has doubled over the last decade, and is associated with high rates of healthcare utilization and high costs of care. Patients with cirrhosis are at risk for liver related complications, particularly hepatic decompensation (e.g., ascites, hepatic encephalopathy, gastrointestinal bleeding) which has high morbidity, low quality of life and increased mortality. Early intervention with specialty care is essential. Presently, we lack effective tools to identify the subset of patients with cirrhosis who are at high risk for decompensation, which would enable prioritization of preventative interventions and increase priority access to specialty care, thus improving overall outcomes. Particularly, we lack validated markers that predict the transition from compensated to decompensated cirrhosis. “Top-down” proteomics (TDP) allows for the direct characterization of proteoforms, which are the molecular variants of proteins. In our preliminary work, a TDP analysis of plasma from a cohort of 30 patients showed that progressive stages of liver cirrhosis could be determined by their patterns of differentially expressed proteoforms (DEPs). We identified 209 DEPs across three stages of cirrhosis (compensated, compensated with portal hypertension, and decompensated). Enrichment analyses of the DEPs suggested that they are involved in several hematological and immunological processes known to be impacted by cirrhosis progression. These data are cross sectional, and prospective data are required to fully understand which changes occur at what time during the progression from compensated cirrhosis to decompensated cirrhosis. To this end, this ancillary study to the NIDDK sponsored Liver Cirrhosis Network (LCN) and approved by the LCN, will examine plasma from 200 of the 1,200 prospectively enrolled and well phenotyped patients with cirrhosis that were prospectively followed for 36 months. We hypothesize that disease progression in patients with compensated cirrhosis is associated with modification of abundant plasma proteoforms associated with coagulation and lipid metabolism. Plasma proteoform composition will provide a sensitive window into early changes in liver status, preceding physiological markers of decompensation, and will allow for risk stratification of decompensation in patients with cirrhosis. The specific aims are: (Aim 1) Provide the molecular basis for understanding personalized progression of liver cirrhosis and selection of candidate markers. (Aim 2) Identify candidate proteoforms associated with probability of decompensation. (Aim 3) Integrate diverse domains of data to identify proteoform changes that precede the functional changes that occur during decompensation. This work will yield fundamentally new knowledge on the molecular foundations of decompensation as reflected in plasma and will advance future work in management and treatment of cirrhosis.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Our work and that of others show that people with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and higher rates of mobility loss than people without PAD. Yet few therapies improve walking impairment or prevent functional decline in people with PAD. In people with PAD, lower extremity ischemia is associated with increased oxidative stress and impaired mitochondrial activity in lower extremity muscle. Nicotine adenine dinucleotide (NAD+) is a coenzyme that is essential for mitochondrial activity. In animals, NAD+ reduces oxidative stress and increases endothelial nitric oxide synthase (eNOS) activity and nitric oxide abundance. In animals, interventions that increase NAD+ abundance improve mitochondrial activity, grip strength, and running endurance. In humans, NAD+ abundance significantly declines with age. Nicotinamide riboside (NR) is a B3 vitamin and precursor to NAD+. In humans, oral ingestion of NR increases intracellular and whole blood abundance of NAD+ in a dose dependent manner. We hypothesize that by increasing NAD+ abundance, NR will improve skeletal muscle mitochondrial activity, reduce oxidative stress, and increase bioavailability of nitric oxide, thereby improving lower extremity perfusion in older people with PAD. Consistent with our hypotheses, our NICE Pilot randomized clinical trial showed that, compared to placebo, NR increased 6-minute walk distance by 17.6 meters and maximal treadmill walking time by 2.1 minutes (i.e. by 28.6%), at 6-month follow-up in people with PAD. In participants with 75% or greater adherence to study pills, NR improved 6-minute walk by 31.0 meters, compared to placebo (P=0.014), an effect size similar to the effects of supervised exercise on 6-minute walk in PAD patients. We now propose a Phase III multi-centered double blinded randomized clinical trial to determine whether NR, compared to placebo, significantly improves 6-minute walk distance at 6-month follow-up in 250 people with PAD. In secondary aims, we will determine whether NR significantly improves calf muscle perfusion (measured by magnetic resonance imaging arterial spin labeling), oxidative stress (measured by plasma oxidized LDL), and mitochondrial activity (measured by oxidative phosphorylation in gastrocnemius muscle biopsies) at 6-month follow-up, compared to placebo. Effects of NAD+ to increase perfusion, reduce oxidative stress, and improve mitochondrial activity directly target the pathophysiologic changes present in PAD. If results from our NICE Pilot Trial are confirmed in this proposed randomized clinical trial, this inexpensive, safe, accessible, and well- tolerated therapy has the potential to meaningfully improve mobility in the large and growing number of older people disabled by PAD.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Therapeutic strategies to halt antibody-mediated rejection (AMR) following lung transplantation are lacking, due in large part to the complex pathophysiology of the immune process and the multi-faceted approach that must be taken to establish a defined diagnosis. It is becoming increasingly clear that AMR has many endotypes, with donor-specific antibodies mediating a host of complement dependent and independent functions. Thus, the development of strategies to stratify patients based upon endotype has the potential to revolutionize the treatment of AMR. Pre-clinically, fluorescence imaging has been used to investigate a wide array of diseases and disorders. In transplantation, the focus has primarily been T cell-mediated rejection, detecting leukocyte trafficking to the graft via phagocyte-specific approaches or fluorogenic probes for inflammatory signatures, such as cathepsin B. In our own previous work, we developed a fluorogenic probe specific to granzyme B and reported its utility in monitoring therapeutic intervention in a murine model of myocarditis, a surrogate for cardiac transplant rejection. As such, there is a great unmet need to develop agents capable of non-invasively diagnosing or monitoring AMR. To this end, we have developed novel fluorogenic probes adept at detecting complement activation in real time, via the examination of complement convertase activity, as opposed to deposition products such as C4d, which persist for weeks at the site of deposition and can only be confirmed by invasive biopsy procedures. Thus, the goals of this proposal are to develop non- or minimally invasive techniques to image ongoing complement activation in-vivo. To accomplish this, we will use murine models of transplant rejection in concert with an assortment of complement inhibitors that act at different points in the complement activation pathway to characterize the extent to which these probes can determine complement activation. We will concomitantly examine their efficacy in a novel porcine ex-vivo perfusion system in which human complement activation can be modeled to investigate the potential clinical applicability in the setting of lung transplantation. To accomplish these goals, we propose the following specific aims: Aim 1: Examination of the extent to which fluorogenic convertase imaging can characterize AMR endotype, and Aim 2: Investigation of the translatability of convertase imaging to the stratification of AMR patients. On the completion of these studies, we will have validated a cadre of novel protease activatable complement specific imaging agents for use in the examination of AMR. We will have further dissected the significance of complement pathway specific proteins in mediating and modulating AMR. By using rodent analogues of clinically available FDA complement inhibitors, should our studies prove efficacious, our results could be rapidly translated.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Neuropsychiatric disorders, prevalent in nearly half of the U.S. population over a lifetime, are increasingly linked to immune dysregulation. Among these, allergic inflammation has emerged as a key contributor, highlighting an understudied connection between the immune system and mental health. Animal models reveal a causal relationship between allergic inflammation and heightened avoidance behaviors, a core symptom of mood and anxiety disorders. Unlike predominantly studied bacterial or viral immune challenges, allergic inflammation represents a distinct T helper cell type 2 (TH2)-mediated response triggered by nonpathogenic environmental stimuli, which activates emotion-related brain centers, including the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). These regions are critical for regulating social and anxiety-like behaviors. Converging evidence positions interleukin-4 (IL-4), a key TH2 cytokine elevated during allergic inflammation, as a potential modulator of mPFC circuits and their projections to the BLA, driving avoidance behaviors. This project seeks to determine how IL-4 impacts mPFC dynamics and contributes to heightened avoidance during allergic inflammation. In Aim 1, we will investigate the quantitative relationship between mPFC IL-4 and avoidance behavior during allergic inflammation, identify local IL-4-producing cell types, and determine the impact of heightened mPFC IL-4 on mPFC-BLA responses during avoidance. In Aim 2, we will examine how IL-4 modulates mPFC microcircuit activity and alters mPFC-BLA output and its contributions to allergic inflammation-induced neuroadaptations, defining its role as a non-classical neuromodulator. In Aim 3, we will test the necessity of mPFC IL-4Rα in allergic inflammation-associated mPFC-BLA responses and avoidance behaviors. By integrating advanced molecular, cellular, and circuit-level approaches, this research will uncover novel cytokine-driven mechanisms underlying behaviors associated with neuropsychiatric disorders and identify new immune-based therapeutic targets to address these complex disorders.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Excess dopamine in the dorsal striatum is thought to be a key driver of schizophrenia. Accordingly, there is a strong corre- lation between the potency of antipsychotic drugs and their affinity for D2 dopamine receptors (D2Rs). However, tradi- tional D2R-binding drugs are not effective for psychosis in ~30% of patients, do not address cognitive and negative symp- toms, and have many adverse effects. Recently, several new therapies have emerged that do not interact with D2Rs. These include promising drugs like xanomeline, an agonist of M1 and M4 acetylcholine receptors. One promise of this new drug class is its potential to work for more patients and address more symptoms than traditional antipsychotics. Capitalizing on this novel therapeutic mechanism requires a deeper understanding of how the drug class works. Recently, our lab used in vivo imaging to determine how two of these drugs (xanomeline and the M4 receptor selective modulator VU0467154) compare to more traditional antipsychotics. Paradoxically, we found that clinical antipsychotic efficacy was more strongly associated with the normalization of activity in striatal neurons that express D1 rather than D2 dopamine receptors (Yun et al., 2023). This was true for both traditional antipsychotics and the newer cholinergic receptor agonists—suggesting the two drug classes may have partly overlapping end effects in the brain. In parallel to these imaging studies, we developed two approaches to selectively activate (either transiently or persistently) dopamine projections to the dorsal striatum. Both approaches affect behavioral processes related to the symptoms of schizophrenia and are compatible with in vivo record- ing. Here will combine these models with in vivo imaging or microdialysis to understand the mechanism-of-action of novel cholinergic antipsychotics and use behavioral testing to explore the range of symptoms for which they may be ef- fective. Specifically, we will use dual-color in vivo imaging to simultaneously record striatal acetylcholine transmission and calcium activity in D1 or D2 receptor-expressing spiny-projection neurons (SPNs). After determining how acetylcho- line relates to D1-/D2-SPN activity and how each relates to locomotor activity, we will activate nigrostriatal dopamine neurons and observe the effects on acetylcholine and D1-/D2-SPN activity. After determining these effects, we will ask how different cholinergic receptor agonists or modulators (xanomeline, M1 agonist, M4 agonist, or an M1 positive allo- steric modulator) affect the relationship between acetylcholine and D1-/D2-SPN activity under normal and hyperdopamin- ergic conditions. The drugs we will test will allow us to directly compare receptor-specific agonism and positive allosteric modulation in isolation or in combination. Next, we will use the same drugs with our animal model of persistent nigrostri- atal dopamine neuron activation. We will use in vivo microdialysis to determine how striatal neurochemistry is altered in these animals and how different cholinergic drugs affect these changes. Finally, we will use behavior (working memory, social exploration, and auditory perception) to determine whether different cholinergic drug types normalize different be- havioral processes in this animal model. Altogether we expect these experiments will advance this new therapeutic strat- egy for psychosis by elucidating the mechanistic basis for its effects on striatal activity, neurochemistry, and behavior. In doing so, we hope to catalyze the development of better and more comprehensive treatments for psychotic disorders.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The rate of food allergy diagnosis in the United States has been increasing over the past few decades, with more than 32 million Americans affected. Food allergies are caused by pathogenic, food-specific immunoglobulin E (IgE) antibodies. It is not fully understood why some people make allergenic IgE food-specific antibodies when the default response to food is oral tolerance. Using a mouse model of oral peanut exposure to screen environmental triggers for their ability to promote the production of food-specific IgE, we discovered that a lipid called alpha-galactosylceramide (α-GalCer) was able to induce anaphylactic peanut-specific IgE. Mechanistically we identified an α-GalCer-dependent pathway that required invariant natural killer T (iNKT) cells, type 2 conventional DCs (cDC2s), and T follicular helper (Tfh) cells for peanut IgE production. Despite evidence that iNKT cells are involved in allergy, mechanisms by which iNKT cell activation leads to IgE to food production are unknown. While α-GalCer itself is unlikely to act as the environmental trigger of food allergy, we hypothesize that specific lipids in the diet or microbiome are presented by gut cDC2s to a subset of pro-allergenic iNKT cells, which promote the priming of Tfh13 cells that drive food-specific IgE. In this proposal, we will define how these three immune cells work in concert to promote the production of food-specific IgE. In addition, we will test if other lipids can promote the production of food-specific IgE, through iNKT and other lipid-restricted T cell mechanisms. In Aim 1 we will determine how iNKT cell activation promotes Tfh cell-dependent food- specific IgE production. Using flow cytometry and single-cell RNA-Sequencing will identify gut iNKT subsets that are activated following oral immunization with α-GalCer and peanut and will determine the cytokines and co- stimulatory signals they produce. In Aim 2 we will test whether exposure to environmental lipids induces food- specific IgE. We will screen naturally occurring lipids from food and microbial sources to determine whether they can activate iNKT cells and promote the production of peanut-specific IgE in a manner similar to α-GalCer. Using human CD1 transgenic mouse model we will also determine whether human CD1-restricted, lipid-specific murine NKT cells can promote peanut-specific IgE responses after peanut and food lipid exposure. In Aim 3 we will identify which antigen presenting cells coordinate the activation of iNKT cells and priming of Tfh cells in the production of iNKT cell-dependent food-specific IgE. Once completed, this work will define the mechanisms of how iNKT cell-induced anaphylactic IgE to food allergens is produced, revealing new cellular pathways that could potentially be targeted to prevent the development of food allergy.

NIH Research Projects · FY 2026 · 2026-03

(PLEASE KEEP IN WORD, DO NOT PDF) Terminal differentiation of erythroid cells occurs in the erythroid-specific niches. The most studied erythroid niche is the erythroblastic island (EBI), which comprises a central macrophage surrounded by developing erythroblasts. While studies over the past decades have identified many genes that are functionally important for EBI, the field faces major caveats. Current knowledge of EBI is predominantly derived from studies of in vitro reconstitution of mixed cell populations that do not recapitulate in vivo niches. In addition, the EBI compositions in human hematopoietic tissues are unknown. In this project, we aim to uncover the anatomy, composition, and functions of EBIs in mice and humans using unbiased approaches through multiple spatial mapping technologies. Through spatial transcriptomic studies, we revealed a higher positive spatial correlation between erythroid cells and C1q+ macrophages than with other macrophages, suggesting that C1q+ macrophages are likely the EBI macrophages in mice. This strong positive correlation between C1q+ macrophages and erythroid cells was also observed in newborn bone marrow and adult spleen under physiologic and stress conditions. We applied the same technologies to human hematopoietic tissues. In contrast to mice, we did not observe a strong positive correlation between erythroid cells and C1q+ or other macrophages in the human hematopoietic tissues. Instead, there is a strong association between erythroid progenitors and maturing erythroid cells. This erythroid self-assembled EBI structure was recapitulated in a human induced pluripotent stem cell (iPSC)-derived bone marrow organoid model. Furthermore, we identified ICAM4 as a critical erythroid surface protein that maintains erythroid-centered EBIs in humans. These preliminary studies uncover unique erythroid niches in mice and humans. Based on this evidence, we hypothesize that mouse and human EBIs have distinct structures and molecular features that help sustain terminal erythropoiesis. In this project, we propose to investigate the composition of macrophage-centered EBIs and the mechanisms of C1q in EBI macrophages in hematopoietic tissues in mice. The same approaches will be used to study ICAM4 and erythroid self-assembled EBIs in humans. Furthermore, EBI responses and their molecular mechanisms under stress and disease conditions in mice and humans will also be investigated. The success of this project will not only advance the understanding of red cell biology but also offer invaluable insights into hematopoiesis as a whole.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Alzheimer's Disease (AD) is characterized by progressive cognitive decline leading to mortality and is a leading cause of death among older adults. The disease involves the formation of plaques and tangles in the brain, which hinder cognitive functioning. Alzheimer's Disease is also associated with sleep architecture, including evidence that alterations in sleep architecture is a predisposing factor for Alzheimer's Disease. There is, indeed, an established relationship between sleep, neurocognition, and brain maintenance, exemplified by the glymphatic system. Research suggests that the glymphatic system helps to clear detrimental proteins from the brain primary during sleep and thus disrupted sleep may hinder this process. Still, we lack a complete understanding of the underlying risk factors and mechanisms for Alzheimer's Disease, which could be improved by the establishment of a network map that connects neurocognitive dimensions, sleep endophenotypes and molecular markers. To address these gaps in knowledge, the proposed project aims to (1) investigate polysomnographic (PSG) sleep biomarkers, proteomic blood biomarkers, and neurocognition in a large longitudinal sample of adults; (2) disentangle the relationship between sleep, neurocognitive function, and circulating proteins using an experimental approach in humans designed to identify proteins that are modulated only by sleep and that are associated with cognitive function, and (3) build a knowledge graph highlighting the three-way relationship between inter-individual variation on circulating proteins, sleep endophenotypes, and changes in cognitive function before and after sleep. The primary hypothesis is that there will be a set of biomolecules associated with neuronal pathways that modulate the relationship between sleep and cognitive decline. A second hypothesis is that this molecular set will significantly share components with biomarkers associated with cognitive decline and dementia. The project includes two distinct studies. The first capitalizes on existing samples and data from a longitudinal study in Brazil, the Baependi Heart Study (BHS) (1R01HL141881) where blood samples were collected before and after a night of sleep recorded via PSG in 2020-2023. We propose to repeat PSG, blood sampling and add new neurocognitive evaluations and AD biomarker in 450 adults who were at least 40 years old at the first PSG recording to provide longitudinal data. We will also repeat the neurocognitive testing 3 years later in these participants. The second study is an experimental study in 50-65 year olds designed to identify sleep-related changes in protein biomarkers that are associated with cognitive function. This experiment involves four controlled 8-hour periods: 8-hour nocturnal sleep opportunity, 8-hour nocturnal wake, 8-hour daytime wake, 8-hour daytime sleep opportunity. Cognitive tests are performed before and after these periods and sleep is recorded with PSG. The results of this study will provide novel mechanistic data linking sleep disruption to the development of Alzheimer's Disease. Further, these protein biomarkers could help identify those at risk of developing neurodegeneration.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Over the past decade, our understanding of regulatory noncoding RNAs (ncRNAs) has expanded significantly, revealing their critical roles in controlling gene expression during development, stress responses, and disease. This project focuses on elucidating the mechanisms driving the biogenesis, regulation, and function of an emerging class of ncRNAs known as downstream-of-gene (DoG) RNAs. Our lab recently identified these unannotated transcripts, which extend beyond the ends of their host genes, exhibit tissue-specific expression patterns, and are induced under transcriptional stress caused by defects in RNA Polymerase II (RNAPII) pausing and Topoisomerase 1 (TOP1) inhibition. Preliminary findings suggest that DoG RNAs may function as long enhancer RNAs (eRNAs), regulating chromatin structure and gene expression through mechanisms that remain unexplored. Building on our prior work characterizing eRNAs and their direct roles in chromatin and gene regulation, this project will investigate the molecular pathways driving DoG RNA biogenesis and processing, as well as their functional roles in transcriptional stress responses and cellular homeostasis. Leveraging advanced genomic, biochemical, and computational approaches, including PRO-seq, RNA-seq, and ChIP-seq, we aim to uncover novel ncRNA-dependent regulatory pathways and elucidate how DoG RNAs modulate chromatin accessibility, transcriptional dynamics, and 3D genome organization. By addressing these fundamental questions, this research will provide critical insights into the biology of stress-induced ncRNAs and their roles in transcriptional fidelity. The findings will not only deepen our understanding of ncRNA-mediated gene regulation but also identify potential therapeutic targets for restoring transcriptional homeostasis in diseases such as cancer, where transcriptional dysregulation plays a central role. This work represents a transformative step in ncRNA research, paving the way for the development of ncRNA- and RNA binding protein-based therapeutics.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Candidate: Roxanna Garcia, MD, MS, MPH is a neurosurgeon and fellowship trained neuro-critical intensivist serving as Assistant Professor of Neurological Surgery at Northwestern University. Dr Garcia’s long-term career goal is to be an independent physician-scientist who uses expertise in implementation research to improve adoption of evidence-based practice in neurosurgical disease, with a focus on traumatic brain injury (TBI) globally. Background: TBI is a public health crisis that disproportionately affects low- and-middle income countries (LMICs), where the risk of mortality is 3 to 4-fold greater than compared to high-income countries. The incidence of TBI represents the leading cause of neurologic disease globally, with approximately 69 million incident cases every year. Moderate TBI (Glasgow Coma Scale[GCS] scores 9-12) and severe TBI (GCS scores 3-8, msTBI) can produce lifelong disability, and is estimated to contribute to over 30% of deaths caused by trauma. Timing to surgery is an important factor, especially among patients with structural lesions. A four- hour timeframe from event to surgical decompression can improve survival. Health system factors delaying timing to intervention have not evaluated, especially in LMICs. Training Plan: In order to achieve research independence, Dr Garcia will need to strengthen skills in (1) applying implementation science methodologies, (2) learning mixed methods to develop (3) expertise in clinical trials research design. Dr Garcia will be mentored by an outstanding multinational team including primary mentor Dr Andrew Naidech (Northwestern University), and Dr Patricia Garcia (Universidad Peruano Cayetano Heredia). Her co-mentors Dr Lisa Hirschhorn (Northwestern University) and Dr Fizan Abdullah (Northwestern University). This team represents experts in health systems and services research, as well implementation science and global health and surgical research. Research Plan: With guidance from her mentor team, Dr Garcia will apply the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework to understand to open cranial surgical intervention for msTBI in the acute emergency setting among health providers in Lima, Peru at high volume trauma centers. The study will continue to build upon an existing prior NIH related post-doctoral research fellowship experience. Dr Garcia will (1) explore the current clinical practices, and define the barriers, and facilitators influencing timing to open cranial surgery for patients suffering from msTBI. She will then apply (2) mechanistic mapping through a co-creation process to create codesign strategies for addressing critical barriers and leveraging facilitators among key stakeholders; and (3) conduct a feasibility implementation pilot to improve timing of open cranial surgery for msTBI. The study will utilize mixed-methods including semi- structured interviews, surveys and focus groups to inform an implementation research logic model and plan, and inform an R01 proposal focused on implementation and sustainment.

NIH Research Projects · FY 2026 · 2026-03

Project Summary / Abstract Depression is one of the most common psychological comorbidities experienced throughout the cancer continuum. Elevated depressive symptoms in oncology patients is a major concern as unmanaged depressive symptoms in cancer patients is associated with poor health-related quality of life (HRQoL), poor adherence to cancer treatments, delayed return to work and baseline function, greater emergency department visits, greater risk of suicide, and higher all-cause mortality. Behavioral interventions for the management of depression are efficacious, but scalability and implementation of these evidence-based interventions in oncology is limited. Health information technologies (HIT) provide an ideal opportunity to expedite the administration, scoring, and interpretation of depression screening with well-validated, brief and precise measurement tools that can capture actionable data to screen for depression, and deliver pragmatic and scalable evidence-based behavioral interventions that are proven to reduce depressive symptomatology across various other populations. Despite the benefits of these HITs, use of technology-based models to screen and deliver evidence-based behavioral treatments that address the depressive symptoms in cancer remains underdeveloped and poorly implemented. We will evaluate the effectiveness and the implementation of an evidence-based HIT behavioral treatment for cancer patients with elevated depressive symptoms. This HIT treatment combines systematic, electronic health record-integrated screening for depressive symptoms with an individually-tailored HIT interventions to address gaps in the treatment of depression among cancer patients. The study takes place across two distinct health systems in two major metropolitan areas—Chicago and Miami (Northwestern Medicine and University of Miami Health System). We aim to conduct a pragmatic Type I effectiveness-implementation hybrid trial of My Cancer Support—an evidence-based, tailored behavioral HIT program for the management of elevated depressive symptoms—in ambulatory oncology care settings within two large health systems. We will establish the effectiveness of My Cancer Support on depressive symptoms(i.e., primary outcome) and anxiety, HRQoL, and health services use (i.e. secondary outcomes) compared to usual care. We will evaluate the process of implementing My Cancer Support and its impact on patient and system-level outcomes, including reach, adoption, maintenance, and acceptability. Next, we will identify facilitators and barriers to wide-scale implementation of My Cancer Support beyond Northwestern Medicine and University of Miami Health System. Finally, we will explore whether the effects of My Cancer Support vary across SES, language, disease severity, severity of depressive symptoms, recruitment sites, and other patient and clinical characteristics.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY The purpose of this Mentored Patient-Oriented Research Career Development Award application is to prepare Brittany Manning, PhD, CCC-SLP, for a career as an independent clinician-scientist with expertise in implementation science. The proposal includes specialized activities, mentorship, and research to support training in (1) community-engaged, co-design methods, (2) clinical trials of early language intervention, and (3) embedded implementation science frameworks. With specialized training in implementation science, Dr. Manning will build on her expertise in the intersection of early language delays and mental health vulnerabilities to adapt and implement interventions to support the complex needs of real-life children with language delays/disorders. Children with language delays are twice as likely to display elevated levels of irritability as their non-language-delayed peers. Elevated child irritability (i.e. a low threshold for frustration and disruptive behaviors) makes it difficult for speech-language pathologists (SLPs) to engage children in language facilitating interactions in intervention sessions. Evidence-based emotion/behavior management techniques are effective in reducing child irritability. However, despite adaptations for other settings (home, school) and implementers (parents, teachers), evidence-based emotion/behavior management techniques and training materials have not been adapted with early language intervention in mind. Thus, the objective of this research proposal is to create SKILL: Supporting Kids with Irritability in Language Learning, an intervention package of adapted emotion/behavior management techniques for early language intervention and a brief, online training for SLPs. Equipping SLPs with evidence-based irritability management techniques is critical for supporting language learning during early language intervention sessions. The research project will pursue the following aims: (1) Using a community-engaged, co-design process, adapt evidence-based emotion/behavior management for early language intervention with iterative input from SLPs, mental health clinicians, and parents; (2) conduct a pilot hybrid effectiveness-implementation type 1 trial to examine the feasibility/acceptability/preliminary effectiveness of SKILL in improving early language intervention outcomes; (3) elucidate barriers/facilitators and implementation strategies to support SKILL’s uptake. Results from the pilot study will inform the optimization of SKILL and the design of subsequent, fully powered hybrid effectiveness-implementation type 1 trial submitted under an R01 mechanism. This work has the potential to improve care for a substantial portion of children with language delays/disorders, improve SLP confidence and satisfaction in working with children with complex needs, and advance implementation science in the field of Communication Disorders.

NIH Research Projects · FY 2025 · 2026-03

Project Summary/Abstract Myocardial infarction (MI) is one of the most prevalent diseases in the United States and worldwide. A characteristic of the post-MI tissue response includes a rapid inflammatory response. The intensity and duration of this inflammatory response are critical in determining extent of death of cardiomyocytes, progression of the immune response towards anti-inflammatory and pro-repair type, and the extent of fibrosis. Hence, inflammation and its timely resolution can affect organism survival, tissue damage and heart function post-injury. Clinically, excessive inflammation has also been shown to be directly correlated to long-term heart failure and mortality after MI. Inflammation-targeting therapies have been tried in the clinical trials, yet we can do better. Following cardiac injury, the inflammatory response includes infiltration of neutrophils and macrophages (Mφ) into the injured tissue. The resolution of this inflammatory response is an active process in which Mφs play a vital role by engulfing dying cells and apoptotic inflammatory immune cells by a process called efferocytosis. This leads to the production of anti-inflammatory cytokines like IL-10, TGF-β, and bioactive lipids like lipoxins. Mφ metabolism is also intertwined with its functional response as inflammatory Mφs prioritize glycolysis while anti-inflammatory Mφs appear to utilize oxidative phosphorylation to a higher degree. The efferocytic Mφ can utilize fatty acids derived from engulfed cells for oxidative metabolism in mitochondria and facilitate repair functions post injury. Peroxisomes are cellular organelles that have important functions in cellular fatty acid sensing and metabolism. These organelles have the unique ability to metabolize very-long-chain fatty acids (VLCFA) in cells. Our preliminary data suggest a spatial localization of peroxisomes surrounding apoptotic cells, as well as induction of peroxisomal β-oxidation and accumulation of VLCFAs in Mφs during efferocytosis. My experiments further imply that VLCFA metabolism regulates cytokine production and polarization of Mφs following efferocytosis. I hypothesize that Mφ peroxisomal VLCFA metabolism regulates the tissue repair response after injury through altering immunometabolic signaling that controls cytokine production, and in turn, the efficiency of organ repair. My hypothesis will be tested through molecular mechanistic studies that identify causal determinants of peroxisomal signaling in Mφs, and consequences on tissue damage, organ function, and inflammation. My studies also have the potential to uncover new targets for the enhancement of the tissue repair.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY / ABSTRACT Stress during early life is an important risk factor for neuropsychiatric disorders, including addiction and depression, but how these experiences produce strong, long-lasting impacts decades into adulthood is poorly understood. To mitigate the harmful effects of early life stress, we need to identify the mechanisms by which transient experiences permanently impinge on circuit function. Since dopamine circuit function is closely tied to addiction and depression, we propose to study this question in the specific context of the dopamine system. We hypothesize that early life experience impacts the trajectory of dopamine circuit development, leading to lasting changes in circuit function. We will use mice as a model system to isolate the effects of early life stress and compare groups of mice exposed to early life stress to those exposed to standard early life conditions or an enrichment condition. We will then track the relationships between dopamine circuit structure and function as individuals mature. In studies spanning from spatial gene expression analyses to anatomy to circuit function and computation, we will systematically determine how transient gene expression changes in specific dopamine subcircuits propagate across development to influence dopamine-dependent behaviors that closely relate to neuropsychiatric risk. In Aim 1, we will use spatial transcriptomic approaches to determine how early life stress impacts gene expression in specific midbrain dopaminergic cell types throughout development and into adulthood. In Aim 2, we will perform complementary studies of dopamine neurite complexity and input connectivity to examine the structural consequences of early life stress-dependent gene expression changes. In Aim 3, we will assay for changes in the informational content of dopamine signals sent to downstream striatal subregions. We will examine the hypothesis that differences in early life experience incur changes in in vivo dopamine release patterns relevant to reinforcement learning. Together, these studies will elucidate how experience during early life developmental periods impacts ongoing adult decision-making well after the cessation of stress. By tying transient gene expression changes during development to lasting structural changes in the dopamine system, we can explain why adult patterns of in vivo dopamine release differ depending on early experience, tying together multiple levels of analysis. A powerful long-term impact of such work will be to inform interventions that address addiction and other neuropsychiatric disorders depending on patients’ life history of experienced stressors.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Immunotherapy has revolutionized the treatment of many tumors. However, most GBM patients have not, so far, benefited from immunotherapeutic treatment. With the goal of exploring ways to boost anti-GBM immunity, we’ve developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism, BAFF and IFNγ stimulation. BVax migrate to key secondary lymphoid organs and are proficient at antigen cross-presentation, which promotes both the survival and functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. We have been successful at generating GBM patient-derived BVax that activated autologous CD8+ T cells, which shows a strong ability to kill autologous glioma cells. This demonstrates that BVax can be produced from patient’s peripheral blood. Our preliminary data obtained under the parental 5R37CA258426 proposal showed that BVax promotes the expansion of clones that differ from CD8 T cells activated by dendritic cells (DC) and the proliferation of stem-like TCF-1+ CD8 T cells. In addition, we provided solid evidence that BVax produces antibodies that react to tumor-associated antigens and inhibit tumor growth. Our central hypothesis is that the BVax have unique properties as antigen-presenting and antibody- producing cells. More specifically, BVax might present a different set of antigens to CD8 T cells. In addition, BVax monoclonal antibodies (mAbs) might have a potential therapeutic effect. This research proposal aims to deep-dive into the immune mechanisms underlying this protection and prevention of tumor growth. We will focus on two processes: antigen presentation and activation of CD8+ T-cell memory formation (Aim 1) and the characterization (sequencing and cloning) of single-BVax monoclonal Ab production (Aim 2). Overall, our study provides a novel alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Pseudomonas aeruginosa (PA) causes over 75,000 nosocomial infections each year in the U.S, and many of these lead to death. Our understanding of how patients acquire PA is rapidly evolving, and it is now apparent that the human gastrointestinal (GI) tract is a major reservoir. Although PA colonization of the GI tract is rare in healthy individuals, it is quite common in hospitalized patients receiving antibiotics. Once colonized, the GI tract contains large numbers of PA and is the source for subsequent spread to other body sites, which in turn leads to infections. This new understanding of PA ecology suggests that strategies to avoid or eradicate GI colonization by PA may prove efficacious in preventing a substantial portion of PA infections in hospitalized patients. In preliminary studies, we have established and characterized a mouse model of PA GI carriage. In this model, PA carriage is absent in untreated mice but occurs in high numbers (~108 CFU/gram feces) following a 7-day course of the antibiotic vancomycin. Interestingly, once established PA maintained carriage for up to 60 days despite cessation of vancomycin administration. We applied a bar-coded PA library to this mouse model and found that PA bacteria encountered a tight bottleneck in the stomach following orogastric inoculation. This bottleneck is largely due to gastric acid and can be overcome by co-inoculation with sodium bicarbonate. Interestingly, the surviving PA bacteria expanded rapidly in the small intestine and caecum over the next several days to numbers that far exceed the initial inoculum. These bacteria moved to the colon and were expelled in the feces. In this proposal, we propose to use this mouse model and corresponding data to better understand how PA establishes carriage. Our hypothesis is that PA produces carriage-facilitating factors that act in the stomach as well as those that act in the intestines and caecum. We propose to use several genetic approaches to identify these factors. These findings will lay the foundation for future studies designed to develop therapeutic inhibitors of these PA factors. Such inhibitors could potentially prevent or eradicate PA carriage and dramatically reduce the burden of multidrug PA infections.

NIH Research Projects · FY 2026 · 2026-02

We aim to continue to longitudinally follow our current cohort study [R01AG058777] (n=293, 94.5% retention rate) to better understand how older adult aging-in-place/long term care (AIP/LTC) decision making, and implementation change over time - impacted by age-related changes (e.g., cognition, function, chronic condition), social influences (e.g., family/friend caregivers), and environmental factors. Remaining in one’s own homes is a priority for many older adults but progressively worsening cognition, seen with Alzheimer’s Dementia (AD), often necessitates support in the home or moving into LTC facilities. Older adults often do not plan for their AIP/LTC needs which leaves families/friends unprepared to handle crises or implement their loved ones’ goals. In our current grant, older adults from an NIA-funded cohort (LitCog) with extensive cognitive testing, were provided with a PCORI-funded intervention (PlanYourLifespan.org - PYL) that facilitates AIP/LTC decision making, at baseline (T0). After the initial intervention, we are following subjects every 6 months through 42 months, with surveys to examine how AIP/LTC decisions are made and implemented. Surveys assess changing subject characteristics, AIP/LTC decisions, implementation, and concordance. Thus far, significant findings have shown: 1.) Older adults require distinctive cognitive subtypes to make AIP/LTC plans (e.g., inductive reasoning, working memory) which may not be detected in conversation or routine memory screening. 2.) Instead of a linear process (pre-contemplative, contemplative, decision), AIP/LTC decision can display circular patterns over a six-month period. 3.) Both external (e.g., social support) and internal (e.g., self-efficacy) factors impact decision making but these variables fluctuate over time. What is missing from this dataset – the gap that we seek to fill – is which variables ultimately impact implementation and whether the AIP/LTC plans of older adults are concordant with the real-world implementation. For this proposal we seek to continue following cohort subjects every 6 months from 48 months to 84 months. Aims are to: 1. Examine how decision making and planning for aging-in-place longitudinally changes over time, impacted by older adults’ age-related changes (e.g., cognition, function), social influences (e.g., offspring), and environments. 2. Assess whether AIP/LTC decision making translates into implementation and goal concordance for older adults and their caregivers. 3. Examine the mediating/moderating interactions between older adult age-related changes, social influences, and environments in planning and implementation for AIP/LTC choices. We will continue to conduct follow-up interviews (every 6 months; months 48 - 84) with our older adult cohort; assessing decision-making, communication, cognition, and health status given in the previous batteries. In addition, we will interview family/friend caregivers for their understanding of the older adults plans and whether implementation of support care has occurred (e.g., adding paid caregivers, moving into memory care facility). Findings have the potential to inform health providers, health care/long term care insurers, caregivers, and older adults nationally in supporting and implementing aging-in-place decisions.

NIH Research Projects · FY 2025 · 2026-02

Neuromyelitis optica (NMO) is an autoantibody-mediated disease of the central nervous system, predominantly affecting women and disproportionately people of African descent. The diagnosis of NMO is contingent upon the accurate detection of the aquaporin-4 (AQP4) antibody, the disease's sensitive and specific biomarker. The availability, accessibility, and affordability of the AQP4 antibody test is low in low- and middle-income countries. Most patients with NMO do not have access to the test globally. Moreover, neuroimmunological disorders have traditionally, but erroneously, been considered to be rare in Black patients, with costly diagnostic tests and even more costly treatments, leading to limited expertise being built in lowest income African settings. Recently, new advances in autoantibody detection using low-cost techniques have emerged, allowing our team to detect the AQP4 antibody from small blood samples that are collected by the patient onto a filter paper-based test and mailed to the processing laboratory. This method allows patients far from reference laboratories to collect a dried blood sample and learn their diagnosis. These samples can be tested from warm temperatures, stored at room temperature, and last months and still be processed successfully. When processed at the Mayo Clinic Laboratories, dried blood spots have a high sensitivity and moderately high specificity for AQP4 detection. The most immediate value for a point of care AQP4 test is in lowest income settings where laboratory capacity is limited and antibody testing is not the current standard of care. In this study, a collaborative team from Massachusetts General Hospital, Mayo Clinic Rochester, and the Ignace Hospital in Guinea with three rural Guinean sites - Dubreka, Fouricariah, and Kindia - will focus on capacity building for neuroimmunological diagnosis and management in the West African Republic of Guinea. The team will test the point of care dried blood spot test in phenotypically-enriched cohorts at highest likelihood of having AQP4 antibody positive NMO in Guinea and estimate point prevalence of NMO in these cohorts. The well-defined subcohort of AQP4+ NMO patients will serve as a base for future clinical trials for the Guinean investigators. The study team will leverage their deep and established expertise to elevate the status of neuroimmunological disease expertise in West Africa. The team will also establish a workflow for testing at the point of care for complex and devastating neuroimmunological diseases, a process that can be eventually scaled for other point of care tests in remote, rural, and/or resource-limited settings.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY The success of solid organ transplantation (Tx) is limited by immune-mediated rejection, with allograft vasculopathy (AV) being a significant cause of long-term graft loss. Endothelial cell (EC) barrier damage inevitably occurring during Tx triggers a cascade of immunological responses culminating in AV. Re- transplantation is the only potential treatment for graft failure from AV. This represents an unmet need for innovative strategies to protect ECs and prevent AV. To address this, we prepared bioactive supramolecular peptide amphiphile nanofibers displaying a fibroblast growth factor-2 mimetic signal (FGF-2 PA). FGF-2 is a therapeutic agent regulating EC barrier function, and PAs are supramolecular nanostructures emerging as promising drug delivery platforms for regenerative medicine. We previously demonstrated the bioactivity of FGF-2 PAs in inducing EC proliferation and migration. Using the murine allogeneic aortic Tx model as a surrogate for studying AV in solid organs, our data demonstrated that ex vivo pre-treatment of donor aortas with FGF-2 PA reduced AV but did not eliminate it. Given the therapeutic potential of FGF-2 PAs, we propose engineering novel supramolecular polymers that display both the FGF-2 mimetic and collagen-binding sequences (cFGF-2 PA). Collagen is the dominant structural component of the EC extracellular matrix and is exposed and immunogenic when the EC barrier is damaged during organ Tx. By targeting the supramolecular nanostructures to exposed collagen in the damaged EC barrier, localized and enhanced bioactivity of FGF-2 can be achieved. Collectively, our data led us to hypothesize that ex vivo pre-treatment of donor allografts with cFGF-2 PAs will protect the EC barrier, thereby mitigating early injury and preventing AV. We propose utilizing an ex vivo pre-treatment strategy, as inevitable damage to the EC barrier in donor allografts occurs during organ procurement and preservation. In Aim 1, the biodistribution, mechanism, and therapeutic efficacy of cFGF-2 PAs in ex vivo pre-treated donor aortas will be investigated to enhance the EC barrier and mitigate early allograft ischemic injury in the murine aortic Tx model. In Aim 2, the therapeutic efficacy of ex vivo pre-treated donor organs will be investigated to prevent AV in murine aortic and heart Tx models. Additionally, its synergistic effect with the recipient sub-therapeutic immunosuppression regimen will be tested to abrogate AV further. Damage to the donor EC barrier is inevitable during Tx, and donor organ pre-treatment regimens are not currently used clinically. Treating the allograft before implantation could minimize the maintenance immunosuppression regimen for the recipient, leading to improved overall graft and patient longevity. Therefore, this study will provide proof of concept and the clinical feasibility of pre-treating donor allografts prior to Tx as a therapeutic strategy to abrogate AV. This study will also support R01-level funding to demonstrate the therapeutic feasibility of maintaining the EC barrier in Tx during organ preservation, leading to a paradigm shift in the current standard of donor organ preservation in Tx.