University Of Pittsburgh At Pittsburgh

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY T cell mitochondrial metabolism is essential for immune cell functions, including immune surveillance and pathogen neutralization. Conversely, impaired mitochondrial function disrupts T cell activity, often resulting in autoimmune diseases, immunodeficiencies, or malignancies. Yet, our understanding of T cell metabolism and its roles in immunologic diseases is poorly understood. Recent work has provided key clues: 1) Disturbances to immune cell metabolic function often result in disease at two opposing ends of the spectrum: cancer and autoimmunity. 2) Rescue of diseased T cell metabolism restores endogenous T cell function, mitigating both cancer and autoimmunity. Moreover, mitochondrial structure and function are intrinsically linked where respiratory complexes do not function in isolation within mitochondria. Rather, these complexes are organized into higher-order assemblies that are concentrated within the cristae and arranged into multi-complex associations of predefined composition, termed supercomplexes. Different disease states not only disrupt the structures of individual complexes but may also alter supercomplex organization to produce symptomatic mitochondrial bioenergetic dysfunction. However, supercomplex formation has never been directly visualized or measured in T cells. I have developed new approaches to directly visualize 3-dimensional mitochondrial structures in healthy and diseased states in patient and animal cells via in situ cryo-electron tomography (cryo- ET). Using biochemical and cryo-ET studies, my goal is to identify the underlying metabolic changes in T cell mitochondrial structure and function during healthy and disease states. I hypothesize: 1) T cell stimulation results in direct structural changes to the respiratory complexes and their higher order organization into supercomplexes; 2) distinct changes in T cell respiratory complex structures contribute to pathologic metabolic dysfunction. To test this, I will identify T cell physiologic mitochondrial ultrastructure and supercomplex stoichiometry (Aim 1) and identify the contributions of T cell mitochondrial ultrastructure and supercomplex stoichiometry within a melanoma tumor microenvironment (Aim 2). Overall, my work will detail how respiratory complexes and their supercomplex organization are regulated in T cells in health and malignancy for the first time. This work may provide a better understanding of T cell pathology, resulting in more effective structure-guided therapeutic interventions. These studies also provide me with training in immunology, biochemistry, and structural biology critical for my development as a physician-scientist.

NIH Research Projects · FY 2026 · 2026-04

SUMMARY Antibiotic resistance is a widespread phenomenon and represents a global threat that is associated with nearly five million deaths a year globally. β-lactams are the most widely used class of antibiotics in treating human infection because of their proven safety and effectiveness. β-lactam resistance refers to the ability of bacteria to withstand the effects of β-lactams. Enzymatic inactivation by β-lactamases is particularly relevant to β- lactam antibiotics as these enzymes hydrolyze the β-lactam ring, thereby rendering them ineffective. AmpC β- lactamases (AmpCs) are produced by most gram-negative bacteria that infect humans including Pseudomonas aeruginosa, and Acinetobacter baumannii, and many species in the order Enterobacterales. They confer resistance to a wide range of β-lactams commonly used to treat bacterial infections and are key drivers of antimicrobial resistance in these bacteria. In general, AmpCs hydrolyze penicillins, cephalosporins and monobactams, and are not inhibited by classic β-lactamase inhibitors (BLIs) but do not confer resistance to carbapenems and to newer β-lactam/BLI combinations such as ceftazidime-avibactam. Extended-spectrum AmpCs display an increased catalytic efficiency toward extended-spectrum cephalosporins and, in some cases, imipenem, the prototypical carbapenem. Extended-spectrum AmpCs may also be less susceptible to inhibition by BLIs. Despite a plethora of studies of AmpC biology, there are several major knowledge gaps. Specifically, all crystal structures of AmpC s in complex with β-lactams or BLIs capture the acyl-enzyme complex, and we lack key insight into the initial binding interactions, intermediate states and kinetic mechanisms associated with the acylation and deacylation steps of the reaction. This knowledge gap significantly limits our understanding of how mutations in extended-spectrum AmpCs confer increased catalytic efficiency toward cephalosporins and/or decrease the inhibitory activity of BLIs. Our central hypothesis is that the application of time-resolved crystallography, coupled with biochemical and microbiological approaches, will provide unprecedented insight into AmpC structure, catalysis and substrate specificity. In Specific Aim 1, we will elucidate the binding, intermediate states and hydrolysis of β-lactam antibiotics by wild type (WT) and extended-spectrum AmpCs. In Specific Aim 2 we will elucidate the reaction mechanisms for BLIs for WT and extended-spectrum AmpCs. The data derived from these Aims will provide a comprehensive understanding for how WT and extended-spectrum AmpC interact with, and hydrolyze, β-lactams and BLIs. This critical insight will ultimately pave the way for developing more effective β-lactam antibiotics and BLIs, which is crucial in the ongoing battle against antibiotic-resistant gram-negative bacteria.

NIH Research Projects · FY 2026 · 2026-04

Abstract Despite advancements in HIV prevention and treatment and the expansion of services, HIV prevalence among men who have sex with men (MSM) in Vietnam has risen dramatically, from 6.6% in 2015 to 12.5% in 2023. Persistent stigmatization of MSM as "social evils," exacerbated by government campaigns associating MSM with the spread of HIV during the early period of HIV epidemic in Vietnam and reinforced by collectivist cultural norms against homosexuality, has exacerbated intersectional stigmas among MSM in Vietnam. This has led to discrimination, fear of disclosure, and avoidance of healthcare services, severely limiting MSM's access to HIV prevention and care services. To address these challenges, this study will culturally adapt a patient-provider stigma-reduction intervention-Finding Respect and Ending Stigma around HIV (FRESH) intervention- into DONGHANH ( meaning “companionship, understanding, and mutual support" in Vietnamese), for implementation among Vietnamese MSM (the patients) and healthcare providers (HCP- the providers). FRESH is a workshop-based intervention that has been successfully used to reduce stigma among healthcare workers and marginalized populations, including MSM, globally. Toward the end of the DONGHANH intervention, participants are expected to work together to develop stigma reduction strategies that they can take back to their respective communities, thus increasing the impact of the intervention. The intervention will also involve the creation of an e-module (a website), allowing participants to determine its delivery and engage in ongoing learning at their convenience. The study will be conducted in three phases: Phase I: using the ADAPT-ITT framework, we will adapt FRESH intervention based on findings from in-depth interviews and focus group discussions to create the culturally tailored DONGHANH intervention. Phase II: We will use a randomized wait-list control trial design to pilot test DONGHANH intervention among 180 participants (MSM=120; HCP=60). Ninety participants (MSM=60, HCPs=30) will participate in the intervention, while the remaining 90 participants (MSM=60, HCPs=30) will be assigned to the 3-month wait-list control. We will assess the intervention’s feasibility, acceptability, and fidelity as well as assess the preliminary efficacy of the intervention on reducing experiences of intersectional stigma and discrimination, increasing HIV testing, PrEP uptake and PrEP/ART adherence. Phase III: We will evaluate assess facilitators and barriers to implementation through interviews with MSM, HCP and project intervention staff, using the Consolidated Framework for Implementation Research to identify contextual factors of the intervention for future scale-up. If the DONGHANH intervention is successful, it can provide a scalable model for reducing intersectional stigmas and improve HIV prevention and care among MSM in Vietnam and other low-and middle- income countries.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Parvalbumin interneurons (PVIs) are essential for regulating cortical network activity, playing key roles in both the primary visual cortex (V1) and in the prefrontal cortex (PFC). PVIs have been implicated in schizophrenia, bipolar disorder, autism, and major depression, with transcriptomic alterations more pronounced than in other neuron types. However, the relationship between these changes in PVIs and corresponding physiological or morphological alterations remains unclear. Assessing these relations is the primary goal of this application. This exploratory R21 proposal investigates, using patch-seq, the properties of PVI subtypes and the effects of social isolation (SI), which induces PVI transcriptome changes in a manner relevant to psychiatric disorders. We will test whether region-specific PVI properties in mouse PFC and V1 contribute to the changes produced by SI. Our pilot studies revealed distinct electrophysiological subtypes of PVIs (continuous firing [cFS] and delayed fast-spiking [dFS]), in PFC and V1, as well as differences in axonal morphology. These baseline differences may contribute to region-specific PVI vulnerability to psychiatric disease or related manipulations. Aim 1 will establish the baseline transcriptomic signatures of PVI subtypes in PFC and V1 under standard group-housed conditions. Using patch-seq, we will integrate single-cell RNA sequencing, electrophysiology, and morphology to define the transcriptional markers distinguishing cFS and dFS subtypes in each region. Aim 2 will determine how SI alters PVI subtypes in PFC and V1 using patch-seq to assess changes in gene expression, excitability, and morphology. By correlating transcriptional changes with cellular phenotypes in the same neurons, this aim will reveal whether region-specific PVI properties shape differential responses to SI. This study is innovative in applying patch-seq to link transcriptional changes to multimodal cellular phenotypes in PVIs. It represents the first investigation of how experimental manipulations affect PVI subtypes across cortical regions. Our findings will provide crucial insights into region-specific PVI dysfunction and generate testable hypotheses on how molecular alterations contribute to disease-relevant cortical circuit changes.

NIH Research Projects · FY 2026 · 2026-04

The Advancing Clinical Translational science for Rehabilitation (ACT4Rehab) research career development program addresses critical gaps in the current NIH portfolio of rehabilitation research. Advancements in the medical management of life-threatening diseases and traumatic injuries are increasing survival and longevity while also increasing the prevalence of chronic illness and physical disabilities. While great rehabilitation research is occurring, rehabilitation translational science is needed to ensure that our health systems and communities deliver the right care to the people who can benefit most from rehabilitation at the right time. ACT4Rehab will create a mentoring network to support a national cohort of rehabilitation clinician scholars capable of becoming independent scientists who lead research programs that restore, increase, and maximize capabilities to positively impact the lives of people with disabilities. ACT4Rehab will conduct widespread outreach to academic and clinical research programs to recruit and select rehabilitation clinician scholars in occupational therapy, physical therapy, and rehabilitation medicine who have an identified scientific domain with high translational potential for clinical implementation. We will train the scholars and their mentors to augment their clinical research expertise with skills in novel intervention research frameworks, study design, and methods; engagement and collaboration practices with shareholders (i.e., the persons for whom the implementation is designed, their families, healthcare providers, health care systems, payors and industry partners); and implementation design and evaluation frameworks, methods, and tools. This training will ensure that ACT4Rehab scholars will be able to advance and accelerate rehabilitation translational science by “designing for implementation” at all stages of intervention development. We will sustain the impact of ACT4Rehab by training mentors and scholars in mentoring best practices to ensure that ACT4Rehab training in clinical research and clinical implementation is available to successive generations of rehabilitation translational scientists. We will further sustain the impact of ACT4Rehab by expanding existing clinical translational science infrastructure to include rehabilitation specific need via establishment of a national ACT4Rehab network with accompanying web-based resources. ACT4Rehab’s impact will be measured by the degree to which we advance and accelerate high quality clinical translational science in rehabilitation to the benefit of society, as measured using the Translational Science Benefit Model.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT: One of the most fundamental limitations in medicine is reliance on clinical phenotype as the primary way to diagnose and classify disease. For inflammatory diseases, clinical phenotype alone is not sufficient to describe underlying disease pathogenesis. For example, cytokines like interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-17A can all drive arthritis, but clinical features such as arthritis or rash may not reflect the causal cytokine. As a result, there are no precision biomarkers to guide targeted cytokine therapy: phenotypic classification systems do not stratify patients by causative mechanisms that guide therapy. The lack of precision medicine strategies is one of the most significant unmet needs in the field, leading to poor outcomes for over 40 million patients with inflammatory diseases. This includes >1 million patients with a phenotype-driven diagnosis of “rheumatoid arthritis”: 40-50% of whom fail first biologic therapy, and 10% with disease refractory to multiple consecutive targeted therapies. We propose addressing this problem by combining expertise in immunogenetics and translational immunology (Dr. Schwartz); systems immunology and machine learning (Dr. Das); and statistical genetics (Dr. Wang).We will leverage another key finding: shared molecular mechanisms like IL-6 signaling can drive different phenotypically defined diseases like arthritis, vasculitis, and scleroderma. Using machine-learning approaches, we will build a phenotype-blind molecular taxonomy for immune diseases. Drawing from the success of phenotype-blind tumor genotyping in cancer therapy, we will adapt machine learning approaches developed in the Das lab to build novel tools (SIDER, Significant Interaction Directional Effect Representation; MAGen Multiscale network Approach for Genetic architecture). We will use SIDER and MAGen to construct an “omnigenic model”, connecting a small number of disease-causal core genes to many peripheral genes through complex biological networks. We will ground our approach in human biology using Dr. Schwartz’s expertise to build on >500 core genes that cause monogenic inborn errors of immunity (IEI). We will use interpretable machine-learning and network approaches developed by Dr. Das to develop molecular modules that will be applied to large population databases leveraging Dr. Wang’s expertise We will investigate two aims: (1) understanding monogenic/oligogenic disease architecture and (2) developing novel molecular endotypes for common diseases. This approach will demonstrate a molecular taxonomy is a relevant and actionable approach that will transform the identification, study, and treatment of immune diseases and beyond.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Rosacea is an inflammatory disorder of the skin that manifests with chronic symptoms including pruritus (itch), rash, and flushing and contributes significantly to patient morbidity. The prevalence of rosacea is estimated to be as high as 20% in some populations. Mast cell activation and degranulation is a key mediator of rosacea symptoms. A growing body of evidence has demonstrated that cutaneous sensory neurons and skin-resident immune cells including mast cells work synergistically to promote local inflammation. For example, pain sensing Trpv1-expressing neurons release the neuropeptide Substance P which activates dermal mast cells via the MrgprB2 receptor. Our recent work has explored the role of a distinct subset of sensory neurons innervating the epidermis, classified as nonpeptidergic type 1 neurons (NP1). In contrast to the mast cell activating capacity of Trpv1 neurons, NP1 neurons suppress mast cell function through the release of the neurotransmitter glutamate which acts directly on mast cells via the kainate receptor GluK2. We have recently found that β-alanine, a known ligand of the NP1 mas related G-protein-coupled receptor D (Mrgprd) that triggers glutamate release, and the small molecule GluK2 receptor agonist SYM2081 both suppressed mast cell-induced inflammation in models of rosacea. Remarkably, in preliminary clinical studies, we have discovered that topical administration of β-alanine suppresses rosacea flushing. Thus, we have discovered a novel neuron-mast cell circuit that regulates cutaneous inflammation. Upon further investigation of this pathway, we have found that abrogation of glutamate release from NP1 neurons augments clearance of epicutaneous Candida albicans infection (a model that is generally thought to be dependent on T cells and not mast cells). Conversely topical SYM2081 treatment induces broad transcriptional changes in multiple immune subsets in the skin. Taken together, our data predicts that NP1-derived glutamate, through its action on mast cells, has broader effects on cutaneous immunity than previously appreciated. We hypothesize that NP1-neuron derived glutamate regulates the responsiveness of mast cells at steady state which subsequently determines the composition of immune cells and functional immune responses in the skin. This proposal will investigate this pathway using transgenic mice that enable us to simulate conditions of low glutamate via the conditional ablation of glutamate release from NP1 neurons (Aim 1) as well as conditions of increased glutamate using direct small molecule agonism of the GluK2 receptor on mast cells (Aim 2). Findings from these studies will provide a mechanistic understanding of how NP1 neurons regulate immunity in the skin. Data generated from this study will have direct clinically translational impact in the treatment of rosacea and other cutaneous inflammatory processes. Contribution to Training: This proposal combines rigorous training in neurogenic inflammation and clinical medicine which will greatly enhance my ability to develop into a highly productive academic physician-scientist.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Phosphoinositide 3-Kinases (PI3Ks) are key regulators of cellular activation, metabolism, and survival, including in lymphocytes like T cells. In recent years, we and others have studied a novel negative regulator of PI3K, which is particularly highly expressed in immune cells, and which we refer to as Transmembrane Inhibitor of PI3K or “TrIP” (gene: PIK3IP1- phosphoinositide-3-kinase interacting protein 1). TrIP contains an extracellular kringle domain and an intracellular p85-like domain. The p85-like domain of TrIP can associate with p110 family catalytic subunits of PI3K, resulting in modulation of the allosteric activation of PI3K by p85α/β adaptor proteins. Conditional KO of TrIP from mouse T cells resulted in enhanced T cell activation and clearance of Listeria infection, as well as enhanced anti-tumor responses. Although there is substantial evidence documenting the negative regulatory role of TrIP on T cell activation, there remain challenges to dissecting the downstream effects of TrIP on the molecular pathways that regulate T cell function. Chief among these is the proteolytically driven down-regulation of TrIP from the surface of activated T cells, i.e. within several hours of stimulation through the TCR. As a result, studies examining the effects of TrIP on TCR signaling, metabolism and gene regulation have thus far been limited by the “moving target” of TrIP expression that changes during the course of activation in WT cells. This makes comparisons to TrIP KO cells more complicated to interpret. We and others recently demonstrated that TrIP downregulation requires TCR signaling-induced cleavage by ADAM10/17 proteases. We have also determined that this cleavage occurs in the “stalk” region of TrIP, which lies between the N-terminal kringle and transmembrane domains, since deletion of part of this domain ablates activation-induced TrIP cleavage. Importantly, this protease-resistant TrIP construct still retains its inhibitory activity, indicating that its function is still intact. With this project, we propose to generate novel genetically modified mice that can inducibly (i.e. in the presence of Cre recombinase) express a mutated form of TrIP that cannot be proteolytically cleaved. We will also perform preliminary analysis of these animals to validate proper expression of the modified TrIP allele and effects on T cell development and activation in vitro.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract In the United States alone, over 250,000 people suffer from Small GTPase (smG) dysfunction linked to cancer, and this number scales to 3.4 million people worldwide. The smG proteins interconvert between the GDP-bound inactive form and the GTP-bound active form, where the active forms bind to effector proteins to trigger downstream signaling. Regulatory proteins such as GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) assist most smG in completing their catalytic cycles. Unlike other smG, RhoA has a unique regulatory process where the Guanine Dissociation Inhibitor (GDI) protein binds the GDP-bound inactive state of RhoA, sequestering it in the cytosol. While there are similarities in the biochemical properties between Ras and Rho proteins, the mutational hotspots in oncogenic RhoA are distinct. Oncogenic gain-of-function mutations of RhoA have been identified in leukemia, lymphoma, and particularly gastric cancer. Although many studies addressed the structure-function relationship of smGs, most structural biology and biophysical approaches employ a reductionist in vitro strategy in which the native environment is ignored. Therefore, there is a gap in understanding how smG performs its activities in its physiological environment and how oncogenic smG behaves in cancer cell environments. In this proposal, I aim to answer three outstanding questions about RhoA function. The hypothesis driving this work is that the mechanism of hydrolysis in oncogenic RhoA is distinct from that in Ras and that the tumor milieu differentially affects conformational states of RhoGTPases. The main objective of this K99/R00 proposal is to develop the tools to study Rho GTPases and exploit them to uncover the activity and regulation of oncogenic RhoA in relevant cancer cell environments and define Rho-GDI interaction as a new therapeutic target. To investigate this hypothesis, during the K99 phase (1) I will elucidate the mechanism of GTP hydrolysis in RhoA and its oncogenic mutants to understand how this is distinct from that in KRas. I will perform time-resolved X-ray crystallography experiments and combine them with NMR- based protein dynamics data to obtain atomic-level details of the transient intermediates formed during GTP hydrolysis; (2) I will answer how cellular environments affect the enzymatic activity of RhoA. Are protein-ligand interactions altered in the cancer cell environment over time? I will implement in-cell NMR and in-organoid NMR methods to measure rates of GTP hydrolysis in gastric tumor cells and protein-ligand binding in gastric-tumor organoids to define these differences in RhoA activity due to changes in the cellular environment. (3 I will interrogate how GDI regulates oncogenic RhoA, identify transient pockets in the RhoA-GDI complex for developing molecular glues that stabilize this interaction, and screen for ligands that bind RhoA in patient-derived organoid models. Upon completion, this work will expand the tools available to study small GTPases in ex-vivo models to target specific oncogenic forms and better understand a key regulatory mechanism in RhoGTPase sequestering. These tools will aid the cancer community, especially the NCI’s Ras Initiative beyond this proposal. My long-term goal is to develop an independent program that connects integrated structural biology with cancer cell metabolism to decipher oncogenic signaling pathways and provide a blueprint for targeting transient pockets in protein-protein interactions.

NIH Research Projects · FY 2026 · 2026-03

CHK1 and WEE1 are critical G2/M checkpoint regulators and therapeutic targets in advanced castration-resistant prostate cancer (aCRPC), including CRPC-Adeno and NEPC. Frequent loss of tumor suppressor genes in these tumors impair G1/S control, creating dependence on the G2/M checkpoint. Targeting CHK1 and WEE1 exploits this vulnerability, but clinical success requires optimized combination strategies, effective delivery, and biomarker-guided patient selection. We propose a novel therapeutic strategy using hyaluronic acid (HA)-based nanocarriers (HASA) co-loaded with CHK1 inhibitor SRA737 (SRA) and WEE1 inhibitor AZD1775 (AZD) for targeted treatment of aCRPC. We demonstrated that the combined inhibition of CHK1 and WEE1 with SRA and AZD resulted in strong synergy in reducing the viability of aCRPC cells and tumor spheroids. In a transgenic NEPC mouse model, the combination of SRA and AZD effectively synergized in suppressing prostate tumor growth and metastasis, highlighting its potential for treating aCRPC. Mechanistically, WEE1 inhibition induced feedback activation of CHK1 and enhanced DNA damage drive their strong synergy in aCRPC cells, and lysine demethylase 5D (KDM5D), an epigenetic regulator frequently deleted in aCRPC, was identified as a novel regulator of SRA sensitivity. To further improve the safety and efficacy of SRA/AZD combination, we developed innovative hyaluronic acid (HA)-based nanocarriers (HASA) for effective codelivery of these drugs to prostate tumors. This delivery platform is highly effective in tumor targeting through the CD44-mediated transcytosis to cross endothelial barriers and accumulate in the tumor site. Our preliminary data confirmed effective loading of both drugs into the nanocarrier, slow kinetics of drug release, selective uptake by tumor cells, and potent efficacy in a syngeneic prostate tumor xenograft model. Thus, we hypothesize that CHK1 and WEE1 inhibitors synergize to disrupt the balance of mitotic control and enhance DNA damage, resulting in robust cell death in aCRPC. Optimized CHK1/WEE1 inhibitor combination based on HASA-mediated codelivery could potentially be leveraged as a safer and more efficacious therapeutic option for lethal prostate cancers. Our study aims to uncover mechanisms of sensitivity for SRA and SRA/AZD combination, and to evaluate the safety and in vivo efficacy of HASA nanocarriers loaded with these drugs in PC models. Two specific aims are proposed: Aim 1. Uncover the mechanisms underlying the varied sensitivity to SRA and its synergistic interaction with AZD in aCRPC cells and tumors. Aim 2. Develop HASA nanocarrier for effective co-delivery of SRA/AZD to improve therapeutic index.

NIH Research Projects · FY 2026 · 2026-03

The regulation of body weight and food intake are under tight control by the hypothalamic circuits in the central nervous system. Perturbations leading to weight gain or loss is usually countered by these circuits to keep body weight within homeostatic limits, a process that is dysregulated in diet induced obesity. This proposal presents preliminary findings suggesting that the epigenetic modifiers in the hypothalamic arcuate nucleus are critical regulators of food intake and body weight. A hypothalamic histone mark on histone H3 correlates with obesity, potentially acting as an epigenetic marker of body weight set point and transcriptional memory of hunger state. Mimicking this change in lean mice by genetic approaches leads to weight gain accompanied by increased food intake or altered energy expenditure depending on the targeted histone modifying enzyme. The epigenetics of the hypothalamic regulation of energy homeostasis at the level of histone modifying enzymes is a relatively underexplored area. Thus, we aim to study the following questions: In Aim 1, we will study the expression level and neuroanatomical distribution of hypothalamic histone methyltransferases and demethylases while trying to understand their response to nutritional and hormonal challenges. We will further conduct a similar mapping for histone H3 lysine methylation. In Aim 2, we will study the role of hypothalamic histone methyltransferases and demethylases in body weight regulation and control of feeding behavior using genetic approaches. We will test if these enzymes could be utilized to alter body weight set point during conditions of energy deficit such as caloric restriction or following GLP-1 agonist-induced weight loss. The role of histone methyltransferases in chemically defined neuronal populations in the hypothalamus will be studied. In Aim 3, we will conduct joint profiling of histone marks and transcriptome profiling at single cell resolution using Paired-Tag. This proposal presents novel regulators of hypothalamic energy homeostasis and offers potential targets for new weight management strategies.

NIH Research Projects · FY 2026 · 2026-03

Suicide is the leading cause of non-accidental death in adolescents in the US, and rates of suicide continue to rise in adolescent populations. Yet, the biological mechanisms leading to adolescent suicide that could inform effective preventive treatments for suicide remain unclear. To understand adolescent suicide, scientists often study suicidal ideation (SI), given that SI is strongly associated with suicidal behavior (SB) and is methodologically more feasible to study in adolescents. This K23 proposal will test a novel and integrative neurobiological model in adolescents with the hypothesis that circulating and stimulated peripheral inflammatory markers (PIMs; e.g. IL-6, TNFα, CRP) contribute to dysfunction in reward-related corticostriatal (CS) circuitry, and that this dysfunction in CS circuitry (and related behavioral correlates) contributes to adolescent SI. Prior research has linked PIM activation to SI/SB, but the biological mechanisms by which PIMs might contribute to SI remain unclear. Existing literature suggests that PIMs might affect CS functional connectivity, and that dysfunction in CS functional connectivity predicts SI and SB, though this integrative model has not been previously tested. Based on conceptual models and early clinical studies, one specific feature of reward processing - effort expenditure for reward (i.e., the amount of effort an individual is willing to expend for a reward) - may specifically be linked to SI/SB. In addition, the described integrative model is particularly relevant in adolescents, who are at a vulnerable developmental epoch for both reward circuitry and immune system maturation. This K23 will test the proposed model in 90 adolescents with unipolar depressive disorders, enriched with adolescents with a history of SI or SB. Adolescents will be followed over four timepoints over twelve months, with measurements of PIMs, CS functional connectivity during a reward task, and SI. This proposal will address key gaps in the field of adolescent suicide research, including understanding (1) the association between PIMs and CS connectivity in predicting future SI, (2) the relationships between PIMs and CS circuitry, and (3) the role of CS circuitry in explaining relationships between PIMs and SI. Understanding these gaps in the literature could elucidate clinically meaningful mechanisms of adolescent suicide, identify biobehavioral markers that could predict future SI, and potentially guide future interventions for adolescent SI/SB. The candidate will receive advanced training from an expert mentorship team, including knowledgeable co-mentors (Drs. Price, Brent, Forbes, and Marsland) and consultants (Drs. Brundin, Treadway, Thoma, and Wallace). The research environment at the University of Pittsburgh provides excellent resources. Consistent with the candidate’s career goals of better understanding biobehavioral mechanisms involved in adolescent suicidality, research findings from this K23 would inform future R01 proposals that could examine mechanisms by which PIMs contribute to SB in large samples, and aid development of interventions targeting PIMs or CS circuitry to reduce SI/SB.

NIH Research Projects · FY 2026 · 2026-03

Abstract Lung cancer is a common and deadly malignancy, accounting for the highest number of cancer-related deaths worldwide. It is divided into two main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Despite groundbreaking advancements in cancer treatment using immune checkpoint blockades (e.g., anti-PD-1/CTLA-4 antibodies), the clinical benefits for lung cancer patients are modest, with a significant fraction of patients failing to respond. Thus, there is an urgent need to improve our understanding of immune evasion mechanisms and develop new therapies to enhance immunotherapy for lung cancer patients. We recently identified KIR+CD8+ T cells as a new type of immunosuppressive cells in humans, which are functional and phenotypic equivalent of Ly49+CD8+ T cells in mice. These cells are elevated in the blood and inflamed tissues of patients with autoimmune or infectious diseases, where they contribute to peripheral tolerance by eliminating pathogenic T cells via their cytolytic activity. Since many tumor antigens are derived from self-molecules, we asked whether these cells are also induced in the tumor microenvironment (TME) to suppress anti-tumor immunity. Our preliminary data showed an increased activity in Ly49+CD8+ T cells in KrasG12DLkb1-/- (KL) NSCLC-bearing mice treated with anti-PD-1 plus anti-CTLA-4 therapy, and depleting these cells significantly enhanced anti-tumor T cell responses in this model. Therefore, we hypothesize that regulatory CD8+ T cells contribute to immune suppression and therapy resistance in lung cancers, and targeting these cells could improve immunotherapy efficacy. To test this hypothesis, we will leverage our innovative murine orthotopic lung cancer models and patient specimens to profile regulatory CD8+ T cells across different lung cancer subtypes and in response to immunotherapy. We will elucidate the mechanisms by which regulatory CD8+ T cells mediate immunosuppression in the TME and assess their potential as therapeutic targets to enhance sensitivity to immunotherapy. Our study may unravel a novel role of regulatory CD8+ T cells in regulating anti-tumor immunity and modulating responses to immunotherapy. By uncovering new cellular dynamics and immunosuppressive mechanisms within the TME, our findings could fundamentally reshape our current understanding on immunosuppression in cancer and support regulatory CD8+ T cells as a new therapeutic target to improve sensitivity to immunotherapy in cancer treatment.

NIH Research Projects · FY 2026 · 2026-03

Aphasia is a language disorder caused by acquired brain injury that affects one third of stroke survivors and more than 2 million people in the United States. Improving mental health is identified as the #1 stroke recovery priority. Stroke survivors with aphasia (SSwA) experience disproportionately poor mental health compared to stroke survivors without aphasia, with high rates of depression, anxiety, and general psychological distress. Poor mental health affects aphasia recovery, and poor aphasia recovery affects mental health. Therefore, mental health services need to be offered as part of comprehensive aphasia rehabilitation to maximize recovery. Adjustment counseling is within the scope of practice for speech-language pathologists (SLPs), who are well-positioned to address the bi-directional relationship between mental health and aphasia as primary providers of interdisciplinary psychological care. Our team has developed Acceptance and Commitment Therapy (ACT) for Aphasia, an integrated aphasia- adapted counseling and communication strategy intervention provided by SLPs. ACT improves psychological flexibility, allowing people to lead lives consistent with their deeply held values, even in the face of persistent psychological distress. ACT pairs well with communication skills training because they help SSwA understand and express themselves during counseling. In turn, ACT helps SSwA become more willing to participate in meaningful life activities and apply communication skills in challenging situations, supporting skill generalization. Our completed Phase I pilot found good intervention acceptability, feasibility, and promising preliminary outcomes, with large effect sizes for reducing psychological distress. This proposal will evaluate the effectiveness of ACT for Aphasia for improving mental health and functional communication in stroke survivors with aphasia. Aim 1 will evaluate ACT for Aphasia via a well-powered Phase II Randomized Controlled Trial. Aim 2 will engage clinician and community end users and healthcare system experts in exploratory implementation research to inform future implementation and intervention refinement. We predict that a) ACT for Aphasia will significantly reduce psychological distress (the primary outcome) and improve functional communication (an exploratory secondary outcome), compared to an active control condition consisting of usual care intervention components, and b) will meet defined benchmarks to justify a large-scale Phase III efficacy trial. Study success will support continued development and evaluation of this novel intervention and determine optimal implementation pathways for improving access to interdisciplinary psychological aphasia care in the United States.

NIH Research Projects · FY 2025 · 2026-03

PROJECT SUMMARY Hospital-acquired pneumonia caused by multidrug-resistant Klebsiella pneumoniae (KP) poses a significant challenge in clinical settings due to limited therapeutic options. Immunotherapy has emerged as a promising strategy against such infections. To inform the development of immunomodulatory therapies to target this pathogen, it is crucial to understand the specific interactions between the immune system and multidrug-resistant KP. The complement system is one of the first lines of defense against bacterial infection. The canonical mechanism by which KP evades complement-mediated killing is through prevention of complement deposition either by modifying its capsule composition to prevent complement deposition or producing more capsule to cover potential complement binding sites on the bacterial membrane. There have been reports, however, of clinical KP isolates that are able to evade complement-mediated lysis despite high levels of complement deposition. The clinical isolates reported to demonstrate this phenomenon belong to the sequence type 258 (ST258). KP ST258 is an epidemic lineage that has caused numerous outbreaks in hospitals around the world. The KP ST258 lineage has diverged into two clades, Clade 1 and Clade 2, that differ primarily in their capsule locus. Clade 2 isolates are found much more frequently in infections than Clade 1 isolates, suggesting that they are more successful pathogens. Notably, in preliminary studies, Clade 2 isolates were found to both bind more C3 complement protein and be more resistant to serum-mediated killing than Clade 1 isolates. This proposal will explore a novel mechanism used by KP to evade complement-mediated killing despite C3 deposition, and will examine if this mechanism results in increased lung injury. Aim 1 will utilize in vitro assays, comparative genomics, and genetic approaches to investigate the requirement for the KP ST258 Clade 2 capsule in this new mechanism of complement-mediated killing. Aim 2 will utilize an in vivo murine model of pneumonia to investigate whether increased complement activation also increases lung injury, and if this can be mitigated through blockade of complement anaphylatoxins. Overall, this proposal will provide new insights into a novel mechanism of complement evasion and will pave the way for the development of targeted immunotherapeutic interventions for pneumonia caused by multidrug-resistant KP. Completion of the proposed training plan under the mentorship of Dr. Daria Van Tyne and Dr. John Alcorn will enable the applicant to develop and refine a wide variety of technical, intellectual, and professional skills that will be instrumental in her future success as an independent investigator and physician scientist.

NIH Research Projects · FY 2025 · 2026-03

PROJECT SUMMARY The ability to seamlessly link individual movements into smooth, efficient sequences is a fundamental aspect of human behavior, enabling everything from speaking to playing musical instruments. This process often feels effortless, yet it relies on complex interactions between different brain regions. When these interactions break down, as seen in movement disorders such as Parkinson’s disease, the ability to learn and execute motor sequences can become severely impaired. The basal ganglia (BG), a set of deep brain structures, is thought to play a key role in this process, but its precise contribution to learning and performance of motor sequences remains unclear. Some prominent theories suggest that the BG store and select well-learned skills, while emerging evidence instead indicates that they act as a tutor, shaping skill learning in the cortex but becoming unnecessary once a skill is well-learned. My project will test these competing ideas by examining how different BG circuits support different stages of motor learning. Using high-density Neuropixel probes, I will record activity from three key cortical regions involved in movement planning and execution—primary motor cortex (M1), supplementary motor area (SMA), and pre-supplementary motor area (pre-SMA)—as well as their anatomically-connected regions in the BG output nucleus, the internal segment of the globus pallidus (GPi). By comparing neural activity during both early learning and well-practiced sequence execution, I will determine how these circuits encode motor sequences over the course of learning at the level of both single-units and neural populations (Aim 1). To test whether these circuits are necessary for learning and recall, I will use pharmacological inactivation with the GABA-A agonist muscimol followed by permanent lesions to disrupt GPi output at different learning stages (Aim 2). This approach will reveal whether the BG is required for learning and performing new sequences but not for executing highly practiced ones, providing insight into how BG circuits interact to shape motor skill acquisition. This fellowship will provide rigorous technical training in multi- area electrophysiology, pharmacological inactivation, and computational analysis of population-level neural data. I will conduct this work within the Systems Neuroscience Institute at the University of Pittsburgh, which offers a uniquely collaborative environment with extensive expertise in nonhuman primate neuroscience. Professional development in mentorship, scientific communication, and leadership will complement my technical training. Together, this research and training plan will prepare me to lead an independent research program focused on the neural basis of skilled behavior.

NIH Research Projects · FY 2026 · 2026-03

Summary This project aims to investigate various aspects of the initiation of DNA replication in human cells. DNA replication is a key process absolutely necessary before each cell division. This process is extremely tightly controlled to ensure its accuracy and timing. The number of licensed origins as well as their firing efficiency defines the ability of cells to timely complete replication, respond to replication stress, and avoid genome instability. Despite recent progress, the initiation of mammalian replication has not been reconstructed in vitro to date, suggesting the existence of origin firing factors and mechanisms that are still not fully described. While in yeast the origins of DNA replication are well defined, their location and regulation in mammalian cells is much more nuanced. Multiple efforts to map origins of replication in cultured cells identified various subsets of replication initiation sites, co-localizing with transcription start sites, as well with G4-structures, lamins, and various chromatin marks. We propose that different subsets of replication origins may require different sets of firing factors for replication initiation, depending on the chromatin context. This project uses a combination of cell biology, genetic, and proteomic approaches to uncover novel factors involved in human origin firing, the order and mechanism of recruitment of specific proteins to the origins, as well as investigates how co-localization of origins with various genomic features affects the mechanisms of their activation. We will use a split-TurboID approach combining transient firing factors with core fork components, as well as location-specific proteins, and identify replication complex (RC)- associated proteins at various stages of origin firing, as well as various chromatin marks and gene elements. We will determine which origin firing factors are common for all replication initiation events, and highlight specific requirements for particular subsets of origins. Given the essential status of the majority of replication proteins, we will leverage mini-auxin-inducible degron system, routinely used in the lab, in combination with cell synchronization approaches, and ATRi-induced massive dormant origin firing, to further investigate the newly discovered firing factors, determine their precise roles in replication initiation, and at which step of the RC assembly/activation they are required. Ultimately, this project will shed light on the complex and diverse process of replication initiation in human cells, and bring us closer to the full understanding of its regulation.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Natural selection is central to many challenges in biology and medicine, from the emergence of drug resistance in pathogens to cancer evolution. Understanding selection can also aid in protein engineering and help identify clinically relevant mutations in human disease genes. Temporal genetic data — sequences and phenotypes sampled over time — can be an especially powerful tool for understanding selection because it allows us to observe evolutionary dynamics directly. But while temporal data from sources like pathogen surveillance, ancient DNA, and experimental evolution have grown tremendously in recent years, statistical analyses of these data remain challenging. My lab will continue to pioneer the development of new computational methods to learn from temporal genetic data, revealing variants and phenotypes under selection and harnessing this information for predictive models of evolution. Over the past five years, we have developed several approaches to quantify selection from temporal data. Thanks to the use of mathematical methods from statistical physics, our methods are fast and accurate despite the inclusion of complex features such as linkage disequilibrium, epistasis, and time-varying selection. We demonstrated the power of these approaches through studies of HIV-1 immune escape and SARS-CoV-2 adaptation during the COVID-19 pandemic, where our analysis identified key mutations affecting viral transmission even before their importance was validated experimentally. Building on this foundation, we will pursue three synergistic research directions: First, we will develop new methods to jointly analyze selection on both individual mutations and phenotypic traits, fusing concepts from population genetics, quantitative genetics, and machine learning. Second, we will apply these methods to study rapid evolution in viral pathogens. Phenotypic models will help us to understand how immune pressure drives antigenic change in respiratory viruses and to compare evolutionary constraints on pathogens across host species. As an ambitious new direction, we will leverage these insights to develop predictive models of pathogen evolution, with influenza as a first target. Our research will systematically identify the features with the greatest power to predict evolution and characterize how and why predictive power may decline over time. Finally, we will extend our approaches to improve the interpretation of high-throughput mutagenesis experiments that measure the effects of thousands of mutations simultaneously. The proposed research will transform our understanding of how selection guides evolution across biological scales, from individual mutations to complex phenotypes, with applications ranging from predicting viral evolution to protein engineering. These advances could ultimately improve our ability to anticipate and control evolutionary processes across a wide range of biological contexts.

NIH Research Projects · FY 2026 · 2026-02

The standard of care for pediatric type 1 diabetes (T1D) is the use of continuous glucose monitoring (CGM) and automated insulin delivery (AID) systems to optimize glycemia. These diabetes technologies hold the potential to decrease the risk of acute and long-term complications. Yet, the rapid developments over the last decade have posed challenges for youth, caregivers, and healthcare professionals who must learn to use these devices. Use of these devices requires significant user interaction and remains labor-intensive, leading to variability in glycemic outcomes. Up to 75% of youth may have higher hemoglobin A1c levels despite device use, placing them at increased risk for complications over time. Schools offer a unique opportunity to support these populations. Youth with T1D spend nearly one third of their weekdays in school under the care of school nurses. School nurses have expressed a critical gap in their knowledge of T1D devices, which can negatively affect parent and student school experiences. To date, little to no research has explored interventions to support school nurses with T1D devices. Structured education may directly impact school nurse CGM and AID knowledge and confidence and student outcomes. e-Learning, defined as the delivery of education through digital resources, allows for flexible, asynchronous learning at a self-determined pace. App-based CGM and AID education stimulates active, problem-centered learning that improves the knowledge and confidence of endocrinology trainees. We propose to adapt an existing diabetes technology e-Learning tool to meet the needs of school nurses using the Discover-Design-Build-Test framework. In the Discover phase (Aim 1), focus groups of school nurses, parents of youth with T1D, teens with T1D, and diabetes clinicians will be used to understand CGM and AID use in the school setting, individual and organizational challenges for school nurses learning to use devices and perceptions of nurse understanding of these devices. The Design and Build phases (Aim 2) will engage school nurses to adapt an existing app-delivered diabetes device curriculum using user-centered design and educational theory. We will conduct usability testing, seeking quantitative and qualitative feedback, to guide app refinement before proceeding to a pilot in Aim 3. Pilot outcomes will focus on feasibility and acceptability (primary), school nurse knowledge and confidence (secondary) and health and academic outcomes for students with T1D cared for by participating school nurses (exploratory). The e-Learning tool developed will be tested in future studies with the goal of implementing a widely disseminatable tool that can lead to sustainable systems-level change to improve school health.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY: SKIN-TARGETED METAL-ORGANIC FRAMEWORK-BASED SUBUNIT VACCINES Driven by their affordability, manufacturability, and safety benefits over traditional vaccines, subunit antigens are an important component of modern vaccinology. However, they exhibit poor immunogenicity and efficacy, and thus, new and rational strategies are required to improve their immunogenicity and efficacy. We propose a novel skin immunization platform (SIP) to address the limitations of vaccine development with subunit antigens. Our innovative and globally deployable SIP leverages emerging vaccine technologies, including (1) metal-organic framework (MOF) nanovaccine constructs; (2) a clinically de-risked adjuvant, and (3) needle-free, thermostable, and self-applied microneedle arrays (MNAs), as well as highly immunoresponsive skin niche for the development of effective and accessible subunit vaccines. The central hypothesis of our project is that in situ harnessing of the immunologically rich milieu of skin with our SIP in a spatially and temporally controlled manner will drive the generation of robust, durable antigen-specific humoral and cellular responses in a well-tolerated manner. Our SIP is engineered in the form of rapidly separable MNAs (rsMNAs) that consist of high-quality obelisk-shaped microneedles comprising dissolving polymer matrix tips loaded with MOF vaccine constructs and non-dissolvable stems with filleted bases attached to the backing layer. Unlike traditional MNAs that require relatively longer wear times (minutes), our rsMNA design, which is enabled by the unique ability of biodegradable MOFs in protecting vaccine components against denaturing organic solvents needed to form non-dissolvable stems of microneedles, facilitates the implantation of MOF vaccines into the skin in less than 10 s via shear force. Our SIP offers the superior vaccine delivery and immunogenicity characteristics compared to needle-and-syringe (N&S) vaccines and conventional MNA-based vaccines. As such, our SIP unlocks the true potential of the skin immune system for improved cutaneous vaccination strategies with subunit antigens. Ultimately, this project will yield a rapidly translatable SIP that will provide unparalleled flexibility and efficacy for vaccination with subunit antigens, which is unattainable with the state-of-the-art immunization platforms.

NIH Research Projects · FY 2026 · 2026-02

7. PROJECT SUMMARY/ABSTRACT Nuclear speckles and paraspeckles are dynamic subnuclear ribonucleoprotein structures that play critical roles in the regulation of gene expression and RNA processing. Increasing evidence suggests that these structures regulate HSV-1 replication in HeLa cells and mouse embryonic fibroblasts (MEFs). However, the mechanisms by which components of nuclear speckles and paraspeckles regulate HSV-1 gene expression in human neurons, as well as their potential role in establishing HSV-1 latency, have yet to be explored. This proposal aims to investigate aspects of the roles played by nuclear speckles and paraspeckles in modulating HSV-1 gene expression in human neurons, as well as to explore how these structures contribute to the establishment and maintenance of HSV-1 latency. In Aim 1, we will investigate whether silencing of paraspeckle-associated genes (NEAT1, PSPC1, NONO, and SFPQ) prevents the silencing of HSV-1 lytic genes and, as a consequence, inhibition of viral replication and suppression of productive infection in our iPSC-derived neuronal model of HSV-1 latency. In Aim 2, we will investigate the involvement of nuclear speckles and paraspeckles in epigenetic modulations of HSV-1 chromatin underlying the establishment of HSV-1 latency. Results from this study will provide essential insights into the role of paraspeckles in regulating HSV-1 infection in human neurons, paving the way for future research and potential clinical applications.

NIH Research Projects · FY 2026 · 2026-02

Abstract. Alzheimer's disease (AD) is the most common neurodegenerative disorder, significantly impacting older adults and placing a substantial economic burden on healthcare systems. Despite extensive research, including numerous clinical trials and drug development efforts, current treatments for AD have shown limited success. Recently approved monoclonal antibodies, while offering disease-modifying potential by clearing Aβ plaques, still face challenges like amyloid-related imaging abnormalities (ARIA) and limited effectiveness due to the complex and multifactorial nature of AD. AD arises from a combination of genetic, environmental, and lifestyle factors, involving multiple pathological processes such as Aβ plaques, tau tangles, neuroinflammation, and neurodegeneration. The biochemical mechanisms of AD are deeply interconnected and dynamic, evolving as the condition progresses, making it difficult for monotherapies to effectively address the disease. Recognizing these complexities, combination therapies are increasingly valued for their comprehensive approach. Gene therapy platforms that target multiple pathways, tackling the diverse factors driving AD, are emerging as promising strategies. Here we propose to develop and refine novel replication-defective (rd) Herpes simplex virus (HSV) vector as gene therapy platform aimed at treating AD. The rdHSV platform is a promising neurotrophic vector with the ability to deliver multiple therapeutic genes, due to its large payload capacity (~35 kb) and ensuring long-term transgene expression through viral and cellular insulators that prevent host silencing. Safety was achieved by removing all immediate early (IE) genes, including those encoding infected cell proteins (ICP) 4, ICP27, and ICP0. These high-capacity vectors, exclusively generated by our laboratory, are supported by preliminary data showing durable (up to 1 year), non-toxic multi-gene expression in the brain positioning it as a potential strategy to address the multifactorial nature of AD. In Aim 1, we will explore the epigenetic mechanisms underlying the interaction between viral and cellular insulators, focusing on how they affect chromatin structure, DNA methylation, and histone modifications. This is crucial for ensuring stable transgene expression in neurons, as controlling the epigenetic environment is key to the long-term success of gene therapy. Enhancing the epigenetic compatibility of the transgene cassette in neurons could also be adapted for use in other CNS cell types in the future. In Aim 2, we will test the therapeutic efficacy of the rdHSV vectors in an in vivo AD model (3×Tg-AD mice), testing the ability of vectors expressing genes targeting Aβ clearance (NEP) and tau degradation (TRIM11). Both genes are downregulated in AD. We will test weather their stable expression will reduce pathology, improve cognitive function, and alleviate neuroinflammation in both preventing and therapeutic settings. We will test the vectors carrying these therapeutic genes, both individually and in combination. By addressing the complex causes of AD, this approach seeks to provide a more effective treatment than the current monogenic therapies that have proven ineffective.

NIH Research Projects · FY 2026 · 2026-02

Each year roughly 500,000 implants are placed in the United States. Of these 500,000 implants approximately 5-10% fail due to a variety of complications, the most common one being peri-implantitis (PI). PI is considered an oral inflammatory condition where accumulation of bacteria on the implant surface leads to a dysbiotic oral microbiome, which triggers inflammation. This persistent inflammation causes an exacerbated host immune response leading to soft tissue damage and alveolar bone loss. Currently, there is no standard of care for the treatment of PI, and much of what we know about PI pathogenesis is in part due to its similarity to periodontitis (PD), an oral inflammatory condition that occurs around a natural tooth. While PD and PI do have some similarities, there remains a lot unknown regarding the pathogenesis of PI, specifically the role of the host immune response. Our group has focused on developing several novel microparticle (MPs) based drug delivery systems that provide local, sustained delivery of cytokines and chemokines. These local drug delivery systems are then able to modulate the host immune response to promote immune homeostasis. In this application, we will utilize two previously developed MPs drug delivery systems: CCL2-MPs to recruit and polarize macrophages towards an anti-inflammatory phenotype and CCL22-MPs to recruit regulatory T cells (Tregs). Promotion of these immunoregulatory cells within the oral cavity may then work to promote resolution of inflammation and immune homeostasis. Preliminary data in this grant demonstrates that there is an impaired healing process in PI and both CCL2 and CCL22-MPs promote immune homeostasis, halt disease progression, and alter the oral microbiome in a ligature-induced murine model of PI; however, the mechanisms in which they promote resolution of inflammation remains elusive. We hypothesize that the impaired healing response is a result of the dysregulated host immune response and dysbiotic oral microbiome and that local immunomodulation allows us to investigate the pathobiology of PI and develop novel therapeutic approaches. To test this hypothesis, we propose the following specific aims: 1) To determine the role of macrophages and neutrophils (innate response) in PI progression and repair; 2) To investigate the role of different T cell populations (adaptive response) in PI progression and resolution; 3) To evaluate the impact of selective antimicrobials on the host immune response. We anticipate that both CCL2 and CCL22-MPs will have a therapeutic benefit (per our preliminary data). Furthermore, as local immunomodulatory approaches halted disease progression and changes in the oral microbiome, we expect to see changes in the frequency and phenotype of different immune cell populations. In sum, our novel immunomodulatory treatments for PI will provide a therapeutic benefit and enable us to further understand the role of the host immune response and oral microbiome in PI progression and resolution.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT This K01 Mentored Research Scientist Development Award will support Dr. J. Travis Donahoe, a health economist and Assistant Professor at the University of Pittsburgh School of Public Health, in becoming an independent investigator whose research advances science about how to reduce substance use-related harm through policies and interventions. The proposed research will apply multiple methods and has three aims: (1) use linked survey and vital records data to overcome key limitations of prior research and identify individual- and neighborhood-level factors that are shaping the fentanyl epidemic; (2) apply quasi-experimental methods to evaluate the effectiveness of demand- and supply-side policies in reducing overdose deaths among high- risk populations; and (3) apply human centered design methods to partner with community experts in two high- risk counties in Pennsylvania and West Virginia—states disproportionately impacted by the opioid epidemic and where Dr. Donahoe’s team has longstanding connections—to co-develop targeted interventions. Complementing his background in economics and quantitative methods, Dr. Donahoe’s career development plan centers on training in social and policy drivers of opioid mortality, population health data and methods, and qualitative and community-engaged intervention development methods. His multidisciplinary mentorship team includes experts in health care delivery for low-income populations (co-primary mentor Dr. Julie Donohue), social epidemiology (co-primary mentor Dr. Christina Mair), qualitative and community-engaged intervention development (co-mentor Dr. Jessica Burke), social demography (co-mentor Dr. Mark Hayward), and population health (co-mentor Dr. David Cutler). Through didactic coursework, guided readings, workshops, conferences, and an apprenticeship, Dr. Donahoe will acquire the interdisciplinary expertise needed to integrate diverse methodological approaches and advance research about how to address both supply- and demand-side drivers of opioid mortality through policies and interventions. Ultimately, this award will position Dr. Donahoe to secure R01 funding to implement and rigorously evaluate novel, data-driven strategies to combat the opioid crisis. By illuminating how supply, social, economic, and policy forces converge to drive overdose risk—and by developing targeted, community-informed solutions— this K01 and the R01 proposals it facilitates will advance the science necessary to reduce opioid-related morbidity and mortality in high-risk American communities.

NIH Research Projects · FY 2026 · 2026-02

The proposed K23 Career Development Award will enable Vikram Raghu, MD, MS, to establish an independent research career focused on improving outcomes in pediatric intestinal failure. Pediatric intestinal failure is a rare, chronic, life-altering condition that requires many children to depend on daily infusions of parenteral nutrition to survive. Complications include life-threatening sepsis events, progressive liver disease, and venous thrombosis, with mortality estimated at over 10% by six years. Despite advances in care, outcomes vary widely, and emerging evidence suggests that geographic and socioeconomic factors strongly influence survival, healthcare use, and quality of life in this population. To address this knowledge gap, Dr. Raghu has assembled a multidisciplinary team of mentors and designed a training program in health disparities research (with a focus on socioeconomic and geographic drivers), multicenter health utility measurement, patient preference elicitation, transplant policy, and leadership in research conduct. These skills will support his overarching goal of optimizing intestinal failure management through decision sciences. The central hypothesis of this project is that variation in outcomes is partly explained by differences in geographic and socioeconomic conditions, such as access to healthcare, school resources, and environmental context, independent of clinical severity. To evaluate this hypothesis, he will accomplish the following specific aims: (1) Identify the effect of the Child Opportunity Index on survival and healthcare utilization in pediatric intestinal failure; (2) Examine socioeconomic and geographic differences in quality of life among children with intestinal failure using the Child Health Utility 9D; and (3) Determine patient and caregiver priorities for addressing socioeconomic and geographic barriers to care through a modified Delphi process and discrete choice experiment. By successfully completing these training objectives and research aims, Dr. Raghu will be positioned to become an independent investigator with the expertise to integrate decision modeling, disparities research, and patient-centered methods to improve outcomes for children with intestinal failure.