Rutgers Biomedical And Health Sciences

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT Treatment for tuberculosis (TB) requires adherence to complex, lengthy, and often toxic multi-drug regimens, which predisposes to treatment failure and relapse. These adverse outcomes appear to be due in part to drug tolerant populations of Mycobacterium tuberculosis (Mtb), the causative agent of TB. Studies of drug tolerant Mtb have been difficult because this phenotype is transient and heterogeneously expressed in populations. We recently discovered a form of drug tolerance caused by phase variation in the Mtb glycerol kinase gene, glpk. Mtb glpK phase variants become drug tolerant via reversible slip strand mispairing of homopolymeric sequences within glpK, causing frame shift mutations that reversibly inactivate the gene. These phase variants are multi- drug tolerant in vitro, re-capitulate classic transcriptional alterations seen in drug tolerant Mtb, accumulate in drug treated mice, have been found in the sputum of patients with multidrug resistant TB, and are associated with decreased drug efficacy. Considerable new data suggests that this form of phase variation is selected for in clinical Mtb strains and thus may be a common cause of clinical drug tolerance. We created an Mtb H37Rv glpK knockout strain which presents us with a unique tool to study clinically relevant forms of drug tolerance. These mutants have phenotypic and transcriptional characteristics similar to glpK phase variants but are genetically more tractable because (unlike phenotypically or phase variant drug tolerant Mtb) these ∆glpK mutants cannot revert to wild type and are thus stable drug tolerant strains, which can be studied in a variety of conditions. We will use this glpK mutant strain to determine the genes and genetic pathways essential for drug tolerance. ∆glpK mutants will be cultured in both standard and media and media modified with different carbon sources including cholesterol to simulate intracellular or granuloma environments. We will then induce macrophages into M0, M1, M2 and foamy states to study how specific host environments affect bacterial drug tolerance and associated transcriptional programs within the bacteria. Together, these studies will identify within pathogen, within host, and host-pathogen interactions that regulate Mtb survival and drug tolerance. Our results will then be used to find potential drug leads that are particularly potent against drug tolerant Mtb in the following aims: Aim 1: Identify the transcriptional and metabolic changes along with related genes essential for the development of drug tolerance in Mtb cultured in physiologically relevant carbon sources. Aim 2: Determine how the interactions between Mtb and the intracellular macrophage environment modulate drug tolerance. Aim 3: Identify preliminary drug candidates with enhanced activity against drug tolerant Mtb.

NIH Research Projects · FY 2026 · 2026-06

Juvenile idiopathic arthritis (JIA) is a chronic illness involving complex treatment plans with varying benefits and risks. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry collects extensive clinical and patient-/parent-reported data on over 12,000 North American children with JIA. However, the Registry lacks data on healthcare utilization, medication dispensing, and patients who do not consent, limiting its utility. Claims databases are large population-based datasets that permit study of large populations, rare diseases, and wide range of outcomes. However, claims data lack potentially critical clinical measures such as disease activity and patient-/parent-reported outcomes. To address these gaps and facilitate future observational and interventional clinical studies, we will perform the Study to Probe & Appraise Registry-Claims Linkage for Juvenile Idiopathic Arthritis (SPARCLe-JIA). This study aims to assess CARRA Registry data linked with the Komodo national claims database (>50,000 children and youth diagnosed with JIA). This linked dataset will allow for a comprehensive evaluation of the Registry's data coverage, consistency, and utility for conducting rigorous and broadly applicable research on JIA. The specific aims are: 1) to compare the characteristics of linked versus unlinked patients with JIA within the Registry and claims data; 2) to compare rates of uveitis and hospitalizations across datasets and evaluate whether use of linked data results in greater validity for an applied question on tumor necrosis factor inhibitors and hospitalized infection; and 3) to investigate how delays in biologic drug dispensing affect subsequent disease activity—a proof-of-concept study that can only be done using linked Registry and claims data. SPARCLe-JIA employs advanced analytical approaches to address critical gaps in pediatric rheumatology research by testing a novel and powerful resource for JIA research. The validation of this linkage between Registry and claims data will set a new standard in the field, providing a model that can readily be applied to other pediatric rheumatic diseases captured by the CARRA Registry, including systemic lupus erythematosus and juvenile dermatomyositis. The linked dataset will enable a wide variety of future investigations, including studies on risk factors, outcomes, healthcare utilization, comparative effectiveness, drug safety, biomarkers, adherence, deprescribing, mental health, and the transition from pediatric to adult rheumatology care, thereby improving JIA management and informing clinical and policy decisions. Through these aims, SPARCLe-JIA will enhance the utility of the CARRA Registry for future observational and interventional studies that will ultimately improve the management, monitoring, and outcomes of people with JIA and other pediatric rheumatic diseases.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Fungal pathogens present a significant risk to immunocompromised individuals because they contribute to increased morbidity and mortality worldwide. Aspergillus fumigatus (Af) is the main cause of invasive pulmonary aspergillosis (IA) and has been identified by the World Health Organization as a critical fungal pathogen for further study. These findings highlight the increasing incidence of IA and the medical need for new strategies to treat invasive fungal infections, such as Af. Myeloid cells, CCR2+ inflammatory monocytes (CCR2+Mo), and neutrophils are necessary for controlling pulmonary Af infection. CCR2⁺Mo gives rise to monocyte-derived dendritic cells (mo-DCs) and alveolar macrophages (AMs), which are key effector populations within the CD11c⁺ cell compartment. In previous studies, we found that CCR2+Mo depleted mice affect neutrophil responses due to a decreased ability of neutrophils to produce reactive oxygen species (ROS) and eliminate Af conidia. Furthermore, neutrophils play a critical role in regulating the antifungal response of CCR2+Mo and promote the differentiation of protective mo-DCs. In previous work to understand the mechanism of monocyte-dependent neutrophil regulation, the lab performed a systems biology approach based on differential neutrophil transcriptomics, which allowed us to identify a strong interferon signaling (IFNs) gene signature. Since STAT1 is key to IFNs, we performed survival studies and found that deleting STAT1 in CCR2+Mo succumbed to Af, impaired maturation of mo-DCs, and reduced ROS formation. Additionally, when we deleted STAT1 in CD11c+ cells, we found that it affected mortality and increased the fungal burden. This confirms that STAT1 expression on CCR2+Mo and CD11c+ cells is required for defense against Af. To assess the importance of Type I IFN, we infected mice with defective expression of the type I IFN receptor (IFNAR1), which developed IA due to their inability to control fungal growth. In a kinetic analysis of IFN-α expression following Af infection, we demonstrated a rapid induction of type I IFN with peak protein expression observed at 12 hours post-infection. Although we have previously shown that type I IFNs are essential for controlling Af, their specific contribution to antifungal immunity in CCR2⁺Mo and CD11c+ cells remains unclear. We hypothesize that type I IFNs are essential for regulating antifungal immunity through CCR2⁺Mo and CD11c+ cells by activating the IFNAR1, triggering STAT1-dependent signaling pathways that enhance defense mechanisms against infections caused by Af. Two specific aims are proposed: 1) to examine the role of type I IFNs in regulating the antifungal response of CCR2⁺Mo and 2) to elucidate the mechanisms of whether type I IFNs regulate the antifungal response of CD11c+ cells. Achieving the proposed objectives will uncover novel insights into how type I IFNs influence antifungal immune responses via CCR2⁺Mo and CD11c+ cells. These findings have the potential to reveal new immunological pathways that strengthen host defenses against Af and inform strategies to improve outcomes in individuals vulnerable to aspergillosis.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY The rapid expansion of the cannabis vape products (CVPs), including both licensed cannabis products and the fast-growing hemp-derived markets, has led to a significant increase in CVP use among young adults (YAs). YAs use CVPs more frequently than older adults, primarily for recreational purposes, which elevates their risk of cannabis dependence, along with various negative health and social consequences. A key factor contributing to this rise in CVP use among YAs is exposure to commercial advertisements (ads) across diverse marketing channels (e.g., billboards, retailers, websites, emails, and social media). However, definitive evidence is lacking on how CVP ads spur YA use—a gap that leaves regulators and prevention programs without the guidance needed to curb the YA-driven surge in CVP uptake. Our scientific premise builds upon existing literature and our own research, suggesting that CVP ads may shape YA behavior through CVP-specific product features that emphasize the functions and benefits of CVP use (e.g., flavor sensation, relaxation, mood enhancement, therapeutic benefits, and reduced harm). We hypothesize that certain CVP-specific product features may be especially effective in generating YAs’ cognitive engagement, increasing positive expectancies and reducing risk perceptions about product use, thereby driving this group’s increased CVP use. The overarching goal of this project is to investigate the impact of CVP ads’ product features on positive expectancies, risk perceptions, and CVP use behaviors among YAs. Aim 1 will involve a large-scale, in-depth content analysis to identify and categorize the product features conveyed in the ads of leading CVP brands (both regular and hemp-derived brands) and across multiple marketing platforms. Aim 2 will employ an in-person eye-tracking experiment with a within-subjects design to measure visual attention in response to viewing product features among 170 YAs. Additionally, we will conduct surveys and in-depth interviews to assess associated perceptions and intentions. Aim 3 will utilize a web-based randomized exposure experiment, employing a 2x2 between-subjects factorial design, to test the independent and combined effects of two high-impact product features on positive expectancies, risk perceptions, and CVP use intentions among 1,980 YAs. We will apply mediation analysis to examine whether expectancies and risk perceptions mediate the relationship between product feature exposure and use intentions. We will also explore the effects on CVP information-seeking behavior and actual CVP use over a two-week period. This project directly addresses NIDA’s priorities by investigating the cannabis industry’s marketing strategies and their influence on use behaviors and motivations. The findings will inform future policy actions regarding CVP marketing in both licensed and hemp-derived markets and contribute to counter- marketing programs aimed at mitigating cannabis-related health risks and addiction.

NIH Research Projects · FY 2026 · 2026-06

PROJECT ABSTRACT Acute respiratory distress syndrome (ARDS) is a severe human manifestation of pathologic acute lung injury (ALI) that develops in some individuals with systemic infection (sepsis). However, it is unclear why only some patients with sepsis develop ARDS. Recent epidemiologic studies have demonstrated a link between exposure to air pollutants, such as ozone and the development of ARDS. Mechanisms underlying this pathologic response and genetic predispositions contributing to this complication of sepsis are unknown and this represents the focus of our studies. ARDS is characterized by an accumulation of activated neutrophils (PMNs) in the lungs. These short-lived cells are normally cleared from inflammatory sites by macrophages as they undergo apoptosis by a phagocytic process referred to as efferocytosis. We found that macrophage efferocytosis is impaired in mice after ozone exposure. Our findings that this is associated with increased numbers of PMNs in the lung during sepsis suggest a mechanism underlying exacerbation of ALI and potentially, the development of ARDS. Surfactant protein D (SP-D) is a pulmonary collectin that blunts alveolar macrophage inflammatory activity; however, this is dependent on the structure of SP-D. Thus, while high molecular weight SP-D multimers are anti-inflammatory, low molecular weight SP-D oligomers are proinflammatory. Approximately 18% of individuals are homozygous for a single nucleotide polymorphism (SNP) in the SP-D gene (SFTPD rs721917;A>G), which is associated increased generation of low molecular weight SP-D oligomers. These low weight proteins activate enzymatic pathways, which cleave the efferocytosis receptor MerTK from the surface of macrophages, a response associated with impaired uptake of apoptotic PMNs. In preliminary human ozone exposure studies, we found that ozone exposure results in MerTK cleavage and that SFTPD rs721917;A>G homozygous individuals have a greater accumulation of lung PMNs following exposure to ozone compared to other SFTPD genotypes. Thus, we hypothesize that individuals homozygous for rs721917;A>G are at increased risk of ARDS after ozone exposure because of increased MerTK cleavage and consequent impairment of efferocytosis. To test this hypothesis, our specific aims are to: (1) Measure alveolar macrophage efferocytosis following controlled exposure of subjects to ozone and the effects of SFTPD genotype on this response, and (2) Determine if SFTPD rs721917;A>G increases the severity of ozone-induced ALI in mice with sepsis. Human subjects will be exposed to air or ozone in a randomized single-blind cross over trial. In parallel experiments, mice with a human SP-D gene with or without rs721917;A>G polymorphisms will be exposed to ozone followed 24 h later by i.v. lipopolysaccharide to induce sepsis. The effects of SFTPD genotype on macrophage efferocytosis, MerTK cleavage, and ALI will be assessed. Our innovative studies will elucidate mechanisms underlying ozone-induced ARDS. They will also help identify humans who are genetically susceptible to the effects of ozone. These discoveries will facilitate approaches to treat efferocytosis dysfunction and prevent ARDS in high-risk individuals.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Adult T-cell Leukemia/Lymphoma (ATLL) is an aggressive T-cell malignancy caused by Human T-cell Lymphotropic Virus Type-1 (HTLV-1) infection. HTLV-1 is endemic to Japan, the Caribbean basin, South America, Eastern Europe and certain areas of Africa. Due to population migration from the Caribbean basin, and South America, there are increasing ATLL patients being treated in the United States. North American ATLL patients (NA-ATLL) exhibit chemo-refractory disease with an overall survival (OS) of only 6.9 months, compared to other ATLL patients (OS of ~1 year). There are currently no effective therapies for ATLL, including the most aggressive forms seen in NA-ATLL. There is an urgent need to understand the mechanisms contributing to severe disease presentation in NA-ATLL to identify new therapeutic targets that could improve overall survival for these patients. A recent study has revealed significant differences in the transcriptional and epigenetic landscape between NA-ATLL and other ATLL patients. In particular, somatic loss-of-function mutations in the E1A binding protein (EP300) have been identified in 20% of NA-ATLL patients. EP300 and its homology CREBB binding protein (CBP), often studied together due to overlapping roles, are major transcriptional co-activators and lysine acetyl transferases. However, genome-wide ChIP-seq studies have revealed distinct binding sites for each protein, indicating that these two proteins may have unique functions in the cell. Our research taking advantage of a unique collection of EP300Mut ATLL cells and an innovative EP300-specific PROTAC degrader shows that reduced EP300 activity is linked to severe dysregulations in DNA replication dynamics, characterized by defective replication fork protection, and the accumulation of cytosolic DNA, which induces cellular toxicity. Moreover, pilot studies show that reduced EP300 is associated with mitochondrial dysfunction and increased oxidative stress. Therefore, the goals of this project are to dissect the mechanisms promoting replicative abnormalities, DNA damage induction and tolerance, in order to identify novel therapeutic strategies for NA- ATLL. In the short term, the knowledge gleaned from these investigations will significantly advance our understanding of NA-ATLL pathophysiology and clarify the mechanistic role of EP300 in the disease. In the long term, we envision that these results will pave the way for leveraging the identified vulnerabilities as therapeutic strategies for NA-ATLL.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY KRAS-driven non-small cell lung cancer (NSCLC) patients are resistant to most therapies, including immune checkpoint blockade (ICB), resulting in poor clinical outcomes. Tumors use diverse strategies for immune evasion, complicating the efficacy of ICB therapies. Oncogene-driven immune evasion involves both intrinsic tumor alterations and extrinsic modulation of the tumor microenvironment (TME). Targeting cancer metabolism, particularly one-carbon metabolism that integrates the folate and methionine cycles, holds promise for enhancing immune responses and improving ICB efficacy. While anti-folates have been used in lung cancer treatment, resistance often limits their effectiveness, driving interest in targeting other key enzymes within one-carbon metabolism. Methionine synthase (MTR), which facilitates the conversion of 5-methyl-tetrahydrofolate to tetrahydrofolate and the regeneration of methionine, is a potential therapeutic target. However, its role in KRAS- driven NSCLC remains poorly understood. We identified MTR as a critical factor for KrasG12D/+;p53-/- (KP) lung cancer cell survival via an in vitro CRISPR screening with a metabolism-focused sgRNA library in a mouse KP lung tumor-derived cell line. Validation studies proved that MTR knockout impaired KP cell proliferation and colony formation, suppressed KP allograft tumor growth in syngeneic C57BL/6 mice, extended mouse survival in genetically engineered mouse models of KRAS-driven lung cancer, and increased tumor CD8 T cell infiltration. Moreover, depletion of both CD4 and CD8 T cells in C57BL/6 mice rescued the growth of MtrKO tumors. These findings highlight MTR’s tumor-promoting role and its link to immune-mediated tumor suppression, suggesting that MTR-mediated tumor metabolism facilitates immune evasion, and targeting MTR may be crucial for enhancing antitumor immunity and improving response to IBC in KRAS-driven NSCLC. To test this hypothesis, we will use KP allograft model and GEMMs to: 1) determine the role of T cell-mediated antitumor immunity in KP lung tumor reduction caused by MTR loss; 2) elucidate the mechanism by which MTR facilitates immune evasion in KP lung tumorigenesis; 3) determine if targeting MTR can enhance the ICB efficacy in treating KP lung cancer, and assess the therapeutic window for systemic MTR inhibition. We expect that these fundamental studies will shed light on the mechanisms by which MTR-mediated metabolic pathways influence antitumor immunity in KP lung tumorigenesis. These will also provide a rationale for combining MTR inhibition with ICB as a therapeutic strategy for KRAS-driven NSCLC. Additionally, this research will offer strong justification for motivating future development of targeted MTR inhibitors for clinical use.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Research experience provides undergraduate students with improved critical thinking, quantitative reasoning, written, oral communication skills vital for their success in competitive higher education programs, as well as for training the next generation of research scientists and medical doctors. This “Research Pathway at Rutgers University, Newark” (RP-RUN) program provides the diverse student population at Rutgers-Newark opportunities to participate in federally funded biomedical research, learning wet- and dry-lab technologies, and developing their professional communication skills. Rutgers-Newark serves the residents of greater Newark and urban northern NJ, is a federally designated Hispanic-serving institution, and the majority of students are first-generation college students. Within the six hundred undergraduate students majoring in Biology, 90% identify themselves as pre-medicine with aspiration for careers in health science related fields. The intellectual focus of this program is on immunological and inflammatory diseases, one of the strongest research areas within the Rutgers Health. Most participating faculty members work on NIAID-funded research. The program will connect the two largest research and teaching enterprises within Newark and will be directed by three established investigators in NJMS and RUN with complementary experiences in education, mentoring, leadership, administration and research. The proposed program is expected to provide full year research exposure to a minimum of 125 motivated students, who will receive hands-on exposure to biomedical research, acquire technical and conceptual skills through advanced imaging camps and multi-omics workshops, and obtain professional guidance on career development. Strong institutional commitment is demonstrated by already committed funds that jump started a pilot program funding 60 students for 3 semesters of research, and continued institutional matching funds provided by both participating units. If successful, this program will allow the Rutgers research and education network in Newark to fully harness its potential as an engine for improving undergraduate access to research and future success in the biomedical ecosystem.

NIH Research Projects · FY 2026 · 2026-05

Project Summary One of the most debilitating aspects of aging is the gradual decline in motor performance, such as coordinated movements and balance. While the cause of motor aging is complex and may rise from changes in multiple peripheral systems, more evidence points to central mechanisms, especially the age-dependent decline in the dopaminergic system. Studies showed that striatal dopamine denervation or reduction in striatal dopamine transporter (DAT) is significantly associated with gait and balance in healthy aging adults. Thus, there’s rising consensus that the aging brain is on the preclinical continuum of Parkinson’s disease (PD). However, it remains to be understood whether PD risk genes contribute to normal age-related motor decline and can be targeted for improving motor abilities in older adults. This project examines the role of a synaptic PD gene, SYNJ1 (murine Synj1), which encodes a lipid phosphatase essential for synaptic membrane trafficking. Our recent studies showed that the dopaminergic synapse rely on Synj1 for axonal surface DAT maintenance. Accordingly, Synj1 deficient mice exhibit lack of surface DAT availability and locomotor deficits, suggesting a Synj1-DAT signaling axis involved in motor control. Our preliminary study showed that loss of Synj1 not only occurs in pathological conditions but is also present during normal aging in both humans and mice. We further found age-dependent loss of Synj1 in striatal dopaminergic terminals, suggesting a potentially pivotal role of Synj1 in age-dependent changes in DAT and motor control. We will test the hypothesis that elevating Synj1 level in DA neurons of adult mice could help improve motor performance and increase striatal/axonal DAT surface expression. We will assess two functional mutants of Synj1 to be compared with WT Synj1, which is expected to bring insights to lipid signaling mechanisms underlie motor control. In Aim 1, we will examine locomotor behavior in an older and a younger cohort to determine whether motor decline during aging can be improved or prevented by Cre-dependent Synj1 expression in DA neurons. In Aim 2, we will determine whether striatal/axonal DAT expression and function can be increased by Cre-dependent Synj1 expression in DA neurons using a combination of biochemical and imaging approaches. Successful completion of the project will reveal the causal role of Synj1 in motor decline during aging and the potential DAT-mediated mechanism and downstream lipid signaling contributing to in this effect. More importantly, it will provide the rationale and proof- of-concept evidence for elevating Synj1 expression as a therapy to improve motor ability in older adults.

NIH Research Projects · FY 2026 · 2026-05

Summary/Abstract: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death in the United States. A better understanding of the mechanisms of CRC will provide novel molecular targets and strategies for CRC therapies. Recent studies suggest that the E3 ubiquitin ligase Parkin plays a crucial role in the suppression of CRC. Parkin expression is frequently downregulated in CRC, and its downregulation is associated with poor prognosis of cancer patients. Currently, the precise role and mechanisms of Parkin in CRC are not well understood, hindering the development of effective therapeutic strategies for CRC. Metabolic reprogramming is a key contributor to cancer progression. Targeting specific metabolic alterations in cancer has become an emerging therapy for cancer. To delineate the novel and critical tumor-suppressive mechanisms of Parkin in CRC and provide novel molecular targets and therapeutic strategies for Parkin-deficient CRC, we employed unbiased screening approaches in our preliminary studies, including LC-MS/MS-based protein-protein interaction analysis and quantitative proteomic analysis. Our preliminary results show that Parkin regulates metabolism through ubiquitination and degradation of key metabolic enzymes in different metabolic pathways in CRC, and furthermore, Parkin deficiency results in the upregulation of these metabolic enzymes and metabolic reprogramming to promote CRC. Notably, targeting these metabolic enzymes and related pathways by specific small molecule inhibitors preferentially suppresses the progression of Parkin-deficient CRC. Based on these preliminary results, we hypothesize that Parkin plays a critical role in the suppression of CRC through ubiquitination of key metabolic enzymes, and Parkin deficiency in CRC leads to the upregulation of these metabolic enzymes and metabolic reprogramming to promote CRC, which can be targeted for therapy. In this proposed study, we will delineate the anti-cancer role and mechanisms of Parkin in CRC and evaluate the novel molecular targets and strategies to treat Parkindeficient CRC. To test our hypothesis, different human CRC cell lines, small molecule inhibitors, orthotopic tumor models, genetically engineered mouse models, and patient-derived CRC organoids will be employed. Mouse models will be used since they are excellent and appropriate in vivo models to study the role and mechanisms of Parkin in CRC and its potential therapeutic application, which cannot be replaced by cultured cells or other in vitro assays in our proposed studies. We anticipate that this study will: 1) delineate the critical anti-cancer role and mechanisms of Parkin in CRC; 2) provide novel mechanisms of metabolic reprogramming in CRC; and 3) provide a strong rationale and proof of concept for developing novel molecular targets and strategies to treat CRC, especially Parkin-deficient CRC, which is urgently needed in the clinic.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Last-resort antibiotics such as polymyxins are paramount in the treatment of multi-drug resistant Gram- negative (GN) bacterial infections. These drugs are understood to exert their antimicrobial effects by associating with the negatively charged phosphate moieties of Lipid A (the lipidic anchor of bacterial lipopolysaccharide in the outer membrane of GN bacteria), disrupting membrane integrity via a detergent-like mode of action. Despite their efficacy, resistance to polymyxins has been observed in pathogenic Enterobacteriaceae such as S. enterica, A. baumannii, K. pneumoniae, and P. aeruginosa via modification of Lipid A phosphate groups with positively charged moieties such as 4-amino-4-deoxy-α-L-arabinopyranose (aminoarabinose or L-Ara4N). In GN bacteria, modification of Lipid A with aminoarabinose is facilitated by an enzymatic relay of eight proteins collectively referred to as the aminoarabinose biosynthetic pathway (ABP). Of these eight proteins, the membrane bound glycosyltransferase, ArnT, the enzyme responsible for catalyzing the last step in the ABP, serves as an attractive target for the development of therapeutic agents capable of reversing polymyxin resistance among various GN bacterial species. The research project detailed in this fellowship application will elucidate key enzymatic residues to better understand the molecular mechanism of ArnT in S. enterica (ArnTSe), identify therapeutic drug candidates for ArnTSe, and test these drug candidates for in vitro antimicrobial activity (Aim 1). Furthermore, we propose to determine the structures of additional divergent ArnT orthologs from clinically relevant species using single-particle cryo-electron microscopy (cryo-EM) and characterize the specificity of drug hits towards different orthologs (Aim 2). Beyond aiding our mechanistic understanding of ArnT’s function, these new cryo-EM structures will extend and strengthen our drug discovery approach. This research project supports the goals of a physician-scientist in training who aims to pursue an academic research career in infectious disease and drug design/discovery. It is expected that the studies supported by this fellowship will advance our mechanistic understanding of ArnT, allow us to structurally characterize clinically relevant orthologs of ArnT, and help us establish a computationally driven rational drug discovery pipeline that can be used to target similar proteins in or outside this biosynthetic pathway.

NIH Research Projects · FY 2026 · 2026-05

Abstract Stroke is a prevalent complication among the over 120,000 Americans with sickle cell disease (SCD), significantly contributing to annual healthcare costs exceeding $2.4 billion. Stroke, including neurocognitive impairment, asymptomatic cerebral infarction, and ischemic or hemorrhagic stroke, is the most frequent neurological side effect in SCD. The nervous system is particularly vulnerable to damage from chronically low hemoglobin (Hgb) levels and repeated vaso-occlusive crises (VOCs), leading to ischemia-reperfusion oxidative stress and inflammation. By age 45, 24% of patients with SCD experience a stroke. Despite this, the underlying mechanisms of stroke and neurocognitive impairment in SCD remain underexplored. Preliminary proteomic studies on platelets from SCD patients revealed significant increases in proteins associated with neurodegeneration, such as α-synuclein (SNCA), amyloid beta precursor protein (APP), and transcription factor p65 (PINK1). These proteins contribute to neuronal damage and the progressive loss of nerve cell function. Mitochondrial dysfunction, particularly reduced mitophagy, is linked to increased levels of mitochondrial proteins and decreased levels of neuroprotective proteins like PARK7 (DJ-1). These proteomic alterations highlight the need for further investigation into the mechanisms driving neurodegeneration and stroke in SCD patients. This study aims to identify the encoded endophenotypes and examine protein interactions related to neurocognitive outcomes in SCD. We will sample 90 sex- and age-matched adults: 30 healthy controls, 30 individuals with SCD and no history of stroke, and 30 individuals with SCD and a history of stroke. Aim 1 will quantify neurodegeneration-associated and mitochondrial proteins in these groups. Aim 2 will examine associations between Hgb levels, neurodegeneration, and cognitive function using neurocognitive questionnaires and NeuroQoL. The impact of this study will extend findings from previous research and help identify specific protein biomarkers associated with neurodegeneration and stroke in SCD patients. This could lead to better diagnostic tools and targeted therapies, ultimately improving patient outcomes and reducing the healthcare burden associated with this severe complication.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT The ASPIRE: Alzheimer’s Summer Program Inspiring Research Engagement (T35 mechanism) at the Krieger Klein Alzheimer’s Research Center at Rutgers is designed to inspire and prepare medical students to pursue careers in bridging ADRD research and clinical care. This summer program offers 10-week, full-time immersive research experiences to 10 medical students per summer, under the mentorship of 10 accomplished scientists. These mentors, with active NIH funding portfolios and proven mentoring success, ensure trainees receive high-quality guidance and sufficient resources. The program will establish internal and external advisory committees to ensure optimal learning goals for the students in ADRD research. Participants will engage in research projects spanning epidemiological observational studies, lifestyle and medication clinical trials, data analyses of "big data" (including “omics” and medical chart data), digital health innovations, and basic science (animal, cellular/molecular, neural stem cell and human postmortem tissue systems studies). This hands-on experience will be complemented by exposure to data science and biostatistics through dedicated meetings with a program biostatistician, equipping students with basic yet practical analytical skills essential for addressing complex challenges in ADRD research. The program emphasizes the responsible conduct of research, including practices that enhance rigor and transparency in human subjects and animals research. Students will also participate in the ADRD Translational Work in Progress series, engaging in open discussions and critiques of scientific materials such as grant aims and hypothesis development. This interactive environment motivates critical thinking, collaboration, and scientific communication skills. Internal and External Advisory Committees, each including world-class researchers in neurodegeneration and ADRD, will meet annually to monitor program progress and provide recommendations for improvement. This oversight ensures alignment with the highest standards of mentorship while maximizing each student’s research experience. The program culminates in a symposium where trainees present their research findings, further refining their scientific communication skills. By exposing medical students to ADRD research early in their clinician careers, the program addresses the critical need for developing future physician-scientists dedicated to ADRD, a condition that disproportionately affects older adults, the fastest-growing segment of the U.S. population. The program aims to cultivate future leaders who will advance innovative research, ultimately promoting state-of-the-art, compassionate care for ADRD patients and improving health outcomes for the rapidly growing geriatric population.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract: This proposal addresses the significant challenge of limited treatment options in inflammatory bowel disease (IBD) and the loss of response to therapies that were previously effective. The long-term objective is to improve the clinical management of IBD by enhancing the initial response to therapy and extending the duration of remission, therein reducing the need for alternative medications or surgical interventions. Specifically, our study will investigate the role of the gut microbiome in modulating the initial effectiveness of anti-TNF therapies, as well as its ability to prevent anti-drug antibody (ADA) development, a common cause of subsequent treatment failure. In Aim 1, we will determine whether the response to anti-TNF therapy induction can be improved by transplanting the gut microbiome of known treatment responders into recipients planning to undergo therapy. Germ-free mice will be colonized with fecal inocula from human patients previously determined to have either responded, or not responded, to anti-TNF therapy. Following the development of intestinal inflammation, the mice will be treated with anti-TNF injections and evaluated for differential treatment response. To assess the robustness of our findings, we will utilize two germ-free IBD mouse models which have been previously demonstrated to be microbiome responsive: the IL-10 knockout and the adoptive T-cell transfer models. Furthermore, emerging studies have shown that exposure to different classes of antibiotics can alter the risk of ADA development among IBD patients treated with anti-TNF therapies. Therefore, our second Aim will be to evaluate if the durability of anti-TNF treatment can be enhanced by the ingestion of microbial communities shaped by antibiotic use. To parallel a future clinical scenario in which microbes may be delivered prophylactically, we will gavage conventional C57Bl/6 mice with microbiomes from mice that have been given various antibiotics. Recipient mice will then be treated with an anti-TNF and subsequently assessed for ADA development. The proposed research will integrate fecal metagenomic, transcriptomic, and metabolomic data to elucidate the molecular basis of the microbiome’s effects. The project endeavors to improve therapeutic strategies for IBD by optimizing the use of anti TNF-inhibitors which are already widely available, therefore offering a scalable approach that can be quickly implemented to address current challenges in IBD care, to guide antibiotic treatment decisions, and to help explain the heterogeneity of anti-TNF response, which has long been clinically recognized but incompletely understood.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT/SUMMARY Tuberculosis (TB) is a leading cause of death in children worldwide, with children contributing to an estimated 14% of global TB deaths and 96% of these deaths being undiagnosed. Children <5 years old have the highest risk of severe disease and mortality and are the most challenging to diagnose, mainly due to paucibacillary disease, non-specific symptoms, and difficulty in expectorating sputum. Innovative and non-sputum-based diagnostic TB tests for this group are needed to reduce childhood TB mortality. Multiple host transcriptomic signatures in blood have been identified for diagnosing pediatric TB, although most have not met the WHO criteria for a pediatric diagnostic test. Transcriptomics on upper airway samples has been used to identify diagnostic biomarkers and study disease pathophysiology for respiratory infections and chronic inflammatory lung conditions. However, no transcriptomic studies are using these specimens for TB. Profiling the upper airway also enables the parallel study of the respiratory microbiome, which has been shown to differ amongst adults with TB disease compared to healthy controls. However, the diagnostic potential of specific microbial communities and their interplay with the host is unexplored in children. With the initial pathogen-host encounter in pulmonary TB occurring in the upper respiratory tract, we hypothesize that detection of host gene expression and the microbiome in the oropharynx and nasal cavity could be used to develop novel diagnostic tests for TB, with the added advantage of using non-invasive and easy to collect specimens. Using already collected samples from two ongoing studies, we propose to perform total RNA-sequencing on nasal brushings and oral swabs collected from children <5 years old with signs and/or symptoms of TB in Uganda (n=150). We will be the first to develop pediatric TB disease diagnostic biomarkers based on detecting upper respiratory tract host gene expression profiles, microbial activity, or a combination. We will also compare our identified nasal and oral host biomarkers to blood host biomarkers to determine how changes in the upper airway reflect those previously found in blood. Finally, we will explore interactions between microbial composition and host gene and pathway expression, increasing our understanding of how microbial communities may influence the host immune response to TB in the upper airways. If successful, our findings will justify larger R01-level studies to validate biomarkers across independent, geographically distinct cohorts for TB diagnosis, as well as mechanistic longitudinal studies focused on investigating causal links between the immune response and the microbiome.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Metastatic breast cancer (mBC) is one of the most devastating diseases. More than 40,000 deaths in the U.S. each year are caused by breast cancer distant metastasis. Triple-negative breast cancer (TNBC) is the most aggressive mBC subtype, with a median overall survival of only 12–18 months. Meanwhile, resistance to treatments occurs in >80% of metastatic TNBC (mTNBC) patients due to the highly dynamic nature of disease progression. These concerning facts underscore the urgent need to enhance understanding of TNBC metastatic mechanisms and identify modifiable factors contributing to the disease burden. One potential key biological contributor and modifiable factor is the microbiome, which has emerged as a potential key player in cancer metastasis. A recent landmark study showed that intratumor microbiota can enter the bloodstream and travel with circulating tumor cells (CTCs) to promote metastasis. Due to the logistical challenges of acquiring repeated tissue and stool samples from cancer patients, studying the blood microbiome alongside CTCs using liquid biopsy samples offers a non-invasive way to assess tumor cells and microbiome features in real-time. However, human blood microbiome studies are extremely limited due to its low-biomass nature and severe interference from host DNA. Recently a novel reduced metagenomic sequencing technique was developed to address these limitations, and we have successfully applied this technique in a preliminary study analyzing longitudinal plasma samples from women with mTNBC. We identified over 15 core microbial species present in plasma, with dynamic changes before and after treatment. Remarkably, we found that low blood microbial diversity was associated with a two-fold increased risk of death, and this risk became even more pronounced when coupled with a high CTC count. Based on these discoveries, we hypothesize that dynamic longitudinal blood microbiome features exist by treatment status, and they can influence mTNBC prognosis directly or through interacting with CTCs. We will characterize the pre-treatment and post-treatment blood microbiome features from the existing ongoing mBC cohort at Thomas Jefferson University (n=200 women, 100 as discovery dataset, 100 as validation dataset). In Aim 1, we will identify baseline blood microbiome features among women with mTNBC and examine the interaction of blood microbiome with CTC in predicting progression-free survival (PFS) across the discovery and validation cohorts. In Aim 2, we will examine the follow-up blood microbiome and CTC signatures and characterize the longitudinal changes of the blood microbiome in predicting mTNBC PFS. We will also compare the profiles between baseline and follow-up signatures and look for changes that are associated with patients’ resistance to their initial treatment. As the first clinical study focusing on blood microbiome in mTNBC, this proposed study will identify longitudinal blood microbial signatures and determine the impact on predicting clinical outcomes with CTC-based liquid biopsy. Successful completion of this study will lead to novel mTNBC disease stratification and the development of microbiome-based strategy for precision treatment and outcome monitoring.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Allergic asthma presents as either T2-high (Th2/eosinophilic) or T2-low (Th17/neutrophilic) inflammation. While external factors like co-stimulation and cytokines shape Th cell fate, the role of T cell receptor (TCR) affinity in directing Th2 vs. Th17 differentiation remains unclear. Our lab developed a fungal protease (Alp1)-driven allergic lung inflammation model and essential reagents, including an IL-5/IL-17A reporter mouse. We observed that Alp1 sensitization primarily induces a Th2 response (~30% IL-5+ Th cells, eosinophilia) but also elicits a smaller Th17 response (~5% IL-17A+ Th cells, neutrophilia). This suggests TCR-intrinsic factors influence effector fate. We hypothesize that TCR affinity dictates Th2 vs. Th17 differentiation in response to fungal protease allergens. A major limitation in allergy research is the lack of tools to study allergen-specific Th cells. We aim to develop peptide-MHCII tetramers to examine TCR affinity and its impact on Th2/Th17 fate within oligoclonal populations. Additionally, we will generate a TCR transgenic mouse and engineered protease allergens to directly test TCR affinity’s role in Th cell differentiation. Our lab has identified an immunodominant Alp1 epitope (aa 194-202) and developed a functional peptide- MHCII tetramer. We also created a transgenic mouse expressing tagged-MHCII in dendritic cells, enabling in vivo epitope discovery. With these tools, we will achieve the following aims: Aim 1: Define the relationship between TCR affinity and Th2/Th17 fate in a polyclonal response. Aim 2: Directly test the causal role of TCR affinity in Th2/Th17 differentiation. This study will advance allergy and immunology research by overcoming technical barriers in epitope discovery and immunodominance. Our transgenic models, cytokine reporters, and tetramer technology will provide a framework for understanding allergen-driven Th cell responses, with implications for new diagnostic and therapeutic strategies in allergic diseases.

NIH Research Projects · FY 2024 · 2026-04

PROJECT SUMMARY / ABSTRACT CD8+ T cells are critical determinants of the anti-tumor immune response. The TCF1+ progenitor-exhausted subset of CD8+ T cells is critical to their therapeutic efficacy, providing a more durable response than their TCF1- more effector-like counterparts. However, the mechanisms underlying the generation and maintenance of this TCF1+ differentiation state remain unclear. T cell metabolism has been intimately linked to differentiation, and recent work from our group and others has begun to interrogate the potential of manipulation of metabolic pathways to alter differentiation. This R03 proposal aims more comprehensively to identify metabolic enzymes controlling the generation of TCF1+ progenitor cells for further functional and mechanistic studies, and characterize key transcriptomic and metabolic characteristics of TCF1+ cells induced under different conditions. The first aim, Identifying metabolic enzymes whose loss results in an altered T cell differentiation state, will interrogate the effect of loss of specific metabolic enzymes on TCF1+ progenitor cell generation across multiple TCR affinities. U-13C glucose stable isotope tracing under different strengths of TCR stimulation and between TCF1+ and TCF1- cells will elucidate differential pathway utilization during T cell activation and differentiation. A CRISPR/Cas9 screen in vitro will target enzymes from pathways upregulated upon T cell activation. Candidate genes regulating TCF1 expression and T cell differentiation will be identified by sequencing and functionally validated by flow cytometric and metabolic analyses. Finally, effects of target manipulation on anti-tumor efficacy will be evaluated in vivo in mice and in an immunocompetent human patient-derived organoid system. The second aim, Identifying transcriptional and metabolic characteristics of TCF1+ progenitor-like cells induced by different metabolic alterations, will determine core properties of these cells. Using drugs and cytokine cocktails known to induce this TCF1+ population through differing mechanisms, activated T cells will be manipulated in vitro to identify transcriptomic and metabolomic similarities and differences. Pharmacological agents targeting hits identified in Aim 1 will also be tested. Data from these aims will allow me to identify both therapeutically targetable nodes for TCF1+ progenitor state induction, and key transcriptional and metabolic characteristics of TCF1+ progenitor cells, including their core characteristics and intrinsic heterogeneity. These data will be leveraged to identify high-quality candidates for future mechanistic studies, and provide a basis for a future R01 submission and career transition from a KL2- supported scholar to an independent investigator.

NIH Research Projects · FY 2026 · 2026-04

Project Summary This project aims to identify approaches for modulating the activity of select potassium (K+) ion channels. A diverse family of K+ channels controls electrical signaling throughout the body, critical for myriad physiological processes. Consequently, K+ channel dysfunction can result in a wide-ranging pathology, both acquired and heritable. In many cases, including rare potassium channelopathies, there are no known targeted therapies, but as the dysfunctional gene and protein is known, these disorders represent tractable biomedical challenges. Here we seek to dissect how key structural properties of select K+ channels govern their functions, and how we can exploit these physical characteristics with novel chemical biology. This program combines studies of three K+ channels, KATP (ATP-sensitive potassium) channels containing the key SUR2 subunit, Kir2.1 channels, and the mechanosensitive TREK subfamily of K2P channels. We will combine patch clamp electrophysiology, with molecular biology and protein engineering approaches, unbiased genetic mutational screening, molecular evolution approaches, and experimental and computational structural biology to define new protein-based and small molecule modulators of these channels. These directions include developing engineered split-SUR2 subunits capable of restoring KATP function in vivo; attempts to identify rescue mutations to compensate for disease-causing variants in Kir2.1; and characterization of a promiscuous drug binding site and the role of the distinctive extracellular cap domain in K2P channels. These studies will provide new insights to how KATP and Kir channels assemble and will identify clinically applicable gene-therapy technologies to treat orphan channelopathies in the future. Further, they will reveal how unique structural features bestow K2P channels with defining pharmacological and functional characteristics. Collectively, over the next five years these studies will build on basic understandings of how these K+ channels form and function and leverage these insights to find new tools to correct molecular dysfunction.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY In 2023, over 9 million adults and 1 million youth in the US reported using cigars in the past 30 days, with most indicating flavor use. Policies restricting the sale of flavored cigars have been adopted across the US to improve public health. However, written policies often do not accurately represent their practical implementation. From an implementation science perspective, there is limited evidence on the extent and effectiveness of existing strategies to implement flavored cigar policies, despite their growing prevalence. The long-term goal of this research is to inform best practices for implementing local public health policies. In this study we will conduct a comprehensive retrospective analysis of real-world policy implementation, capitalizing on a natural experiment to enrich our understanding of the policy implementation process and identify strategies that curtail cigar sales and consumption. The scientific premise is based on (1) demonstrated efficacy of flavored cigar policies in limiting access to a widely appealing product, (2) research noting limitations in the implementation of flavored cigar policies that may impact outcomes, (3) implementation science theoretical frameworks indicating the importance of the implementation process when assessing policy outcomes, and (4) preliminary data indicating heterogeneity in policy implementation strategies across municipalities. This study will provide critical data on the implementation of flavored cigar policies in the US, to inform the knowledge base on how policies are implemented, and which strategies reduce cigar sales and use. More broadly, this study will advance the field of dissemination and implementation science by creating a policy implementation measure that accounts for differential implementation and can be used to inform more rigorous policy evaluations.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The focus of this application is to understand the integrated metabolic regulation of wound healing. Productive tissue repair is a fundamental requirement for an organism to maintain tissue homeostasis and organ function. Dysregulated wound healing is relevant to various human diseases, including heart disease, autoimmune diseases, chronic wounds, cancer, and infection. Tissue repair requires the coordinated action of multiple cell types, including immune and stromal cells, through several phases of wound healing that take days to months. Intracellular metabolism is a central regulator of cellular effector functions and has become a therapeutic target to modulate disease progression and patient outcome. Despite the progress in understanding the signaling networks that regulate wound healing, the metabolic regulation of wound healing in vivo remains poorly understood. Key gaps include understanding how the intracellular metabolism of individual cells is regulated to influence effector functions and how metabolic crosstalk between different cell types is coordinated for productive wound healing. We use zebrafish (Danio rerio) as our in vivo model of inflammation and tissue repair. The optical transparency, ease of genetic manipulation, and high similarity to the human immune system and genome make zebrafish an ideal model for dissecting multi-cellular interactions during tissue repair in situ. We have shown that fluorescence lifetime imaging microscopy (FLIM) of endogenous metabolic coenzymes, nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD) are sensitive to dynamic changes in the intracellular metabolism of macrophages during wound responses in live zebrafish larvae. We will continue implementing FLIM modalities and analytical tools to enable the spatiotemporal analysis of intracellular metabolism in native interstitial spaces in a living animal. We found that mitochondrial ROS contributes to macrophage metabolism during the early pro-inflammatory phase of wound response. We will employ single cell-based imaging, including FLIM and fluorescent metabolic sensors using standard confocal microscopy, and spatial metabolomics to dissect the role of canonical and non-canonical pathways in mitochondrial function to regulate innate immunity and interaction with epithelial cells during tissue repair. Our studies will contribute to a better understanding of the metabolic regulation of tissue repair and may provide new targets to treat human disease.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT In this grant cycle, Rutgers Cancer Institute had an unprecedented opportunity to expand clinical research to a significant number of additional hospitals of the RWJBarnabas Health (RWJBH) system. This unified and organized expansion was enabled by 1) Dr. Libutti’s roles as Cancer Center Director and Senior VP for Oncology Services of RWJBH; 2) Dr. Hochster’s roles as Rutgers Cancer Institute Associate Director for Clinical Research and Director of Oncology Research for RWJBH; and 3) development of a system-wide academic health system between Rutgers and RWJBH effective 01/01/2019 through a Master Affiliation Agreement. In this newly integrated and unified “one-site” model, Rutgers Cancer Institute has an unprecedented number of patients at its disposal for clinical research activities to impact the catchment areas' priorities and needs positively. The Office of Human Research Services (OHRS) serves as a centralized research administration, housing all administrative tasks at Rutgers Cancer Institute while providing oversight and direction for each clinical oncology research operation site throughout RWJBH. OHRS is responsible for working with Rutgers and system-wide clinical investigators to manage the business, clinical, and regulatory functions of all phases of pediatric and adult oncology cancer clinical trials throughout the health system. Our model is “one site with one CTMS, one IRB, and one EMR’, which is currently operational. The organizational structure, which reports to Drs. Libutti and Hochster is comprised of 158 FTEs with ten distinct offices divided and based on specialization within functional areas such as clinical operations, quality assurance, and regulatory affairs. In parallel with the growth of Rutgers Cancer Institute, screening, enrollment, and the number of available NCTN clinical trials increased significantly with the integration of RWJBH health system sites into OHRS. To date, the number of open trials has more than doubled (52 vs. 24 in 2019), and enrollments in NCTN clinical trials have increased by more than 500% (662 vs. 132). Minority enrollment has steadily increased from 29.9% in 2019 to 41.3% in 2024 over the grant period. During the current grant period, therapeutic trial accrual has risen by more than 400% (552 vs.132). In recent years, Rutgers investigators have held prominent roles within ECOG-ACRIN, NRG, and Alliance. Evidence of our success in scientific contributions is reflected in our investigators' significant leadership roles, memberships in key group studies, and authorship of numerous publications stemming from NCT trial participation. Moreover, Rutgers consistently mentors and engages young investigators in clinical trial research, as demonstrated by the recent appointment of two junior investigators who have assumed leadership roles in ECOG-ACRIN clinical trials.

NIH Research Projects · FY 2026 · 2026-03

Menopause and estrogen deficiency increase the risk of insulin resistance and metabolic diseases in women, but the mechanisms remain unclear. Targeted therapies for menopause associated insulin resistance are lacking, with estrogen replacement increasing the risk of certain malignancies. Estrogen deficiency leads to sympathetic nervous system (SNS) overdrive but implications on metabolic health remain unexplored. Our preliminary studies in mice demonstrate that ovariectomy (OVX), a model of estrogen deficiency-induced insulin resistance, increases plasma norepinephrine and sympathetic nervous system activity (SNA) in white adipose tissue. Suppression of sympathetic norepinephrine release attenuates insulin resistance after OVX and improves other manifestations of the metabolic syndrome such as adipose tissue dysfunction and hepatic steatosis. Based on these findings, we will test the hypothesis that SNS overactivity disrupts insulin’s ability to regulate glucose production in the liver and lipolysis in white adipose tissue and hence that interventions that attenuate the SNS overdrive are a promising therapeutic strategy to improve metabolic health in postmenopausal women. The proposed studies will employ innovative gain- and loss-of-function models to manipulate SNA at an organismal and tissue-specific level and clarify what drives increased SNA in estrogen deficiency, how SNS overdrive induces insulin resistance, and whether sympatholytic interventions are effective to improve metabolic control. We examine this in two specific aims. Aim 1 focuses on understanding how estrogen deficiency alters SNS activity and impairs insulin action. We will examine how OVX alters SNA to different metabolic organs, assess its impact on cellular insulin signaling, and test whether increased SNA alone, independent of estrogen deficiency, is sufficient to induce metabolic disease in female mice. Aim 2 will characterize how changes in SNA modulate insulin sensitivity and nutrient fluxes in estrogen deficiency. We will test whether limiting norepinephrine release from the SNS in all peripheral tissues and in adipose tissue specifically or employing other sympatholytic interventions can prevent OVX-induced insulin resistance. These studies will offer new insights into mechanisms of insulin resistance in estrogen deficiency and pave the way for the development of targeted strategies to treat metabolic diseases in postmenopausal women.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Career Goal: My career goal is to become a leading independent investigator contributing rigorous social science research to understand cognitive health differences among the growing population of older immigrants in the US. With the immigrant population 65 and older expected to double to 20 million by 2050, investigating the ways modifiable risk factors for Alzheimer’s disease (AD) and Alzheimer’s disease and related dementias (ADRD) operate for immigrant populations is an imperative area of research. Training towards content area and methodological expertise will enable me to contribute to scholarship aimed at reducing the public burden of AD/ADRD in a growing US population. Career Development: I will undertake four training aims to enhance my knowledge and skills in (1) the biological and social pathways shaping AD/ADRD, (2) geriatric mental health and social relationships, (3) epidemiological causal inference, and (4) professional development for becoming an independent investigator. Research Project: Mexican immigrants, the largest group of immigrants in the US, are rapidly aging, but current research often aggregates US Latinos, overlooking origin- and nativity-specific social, structural, and migration-related factors that influence AD/ADRD risk. Attention to specific immigrant populations is necessary to address heterogeneity in cognitive risk factors. To address this gap, the proposed research focuses on loneliness, a risk factor for AD/ADRD that may be heightened in the older Mexican immigrant population. Using data from a nationally representative panel survey, complemented by data from a Rutgers-based cohort that collects advanced biomarkers, the proposed project uses causal inference to analyze the inter-relationship between loneliness, social relationships, inflammation, and cognition for Mexican immigrants in the US compared to non-migrants, advancing understandings of modifiable risk factors for AD/ADRD. Specific Aims: (1/K99) Determine loneliness trajectories, social relationship risk factors for loneliness, and the contribution of loneliness to cognitive functioning in the Mexican immigrant population compared to non-migrants. (2/R00) Quantify inflammation as a mediator in the loneliness-cognition pathway in the Mexican immigrant population compared to non-migrants. (3/R00) Characterize the loneliness- inflammation and loneliness-AD/ADRD relationships in the Mexican immigrant population compared to non- migrants using advanced biomarker data. Mentorship: A complementary set of accomplished experts in AD/ADRD, geriatric mental health, social networks, immigrant health, biomarker analysis, and causal inference will provide training and professional mentorship to ensure my successful transition to independent investigator. Future Directions: With the proposed training and research experience, I will have a unique combination of substantive expertise and methodological skills to become an independent scientist and submit successful R01 proposals to examine AD/ADRD social determinants among high-risk subpopulations.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Micro-nano-plastics (MNPs) are small plastic particles resulting from the environmental breakdown of plastic waste over time. These particles have accumulated in ecosystems and entered the food web through contaminated water and food, trophic transfer, and exposure during food processing and packaging. Recent studies have detected MNPs in nearly every human organ and tissue, underscoring their widespread presence. While it is known that MNPs can cross biological barriers like the intestine, the health effects of MNP exposure are still poorly understood, and the mechanisms that allow MNPs to bypass these barriers remain unclear. Additionally, most toxicological studies have relied on simplified MNP models, such as polystyrene beads, which do not accurately reflect the complex physicochemical properties of real-world MNPs. This project aims to bridge these knowledge gaps by exploring the intestinal uptake mechanisms, biodistribution, and impacts on intestinal health of environmentally relevant MNPs. The focus will be on the effects of MNP polymer type, size, surface chemistry (including weathering), and prolonged exposure on MNP toxicity and inflammatory responses. Our central hypotheses are: (I) MNP properties such as size, polymer type, and environmental weathering influence their uptake, translocation, toxicity, and inflammatory effects; (II) MNPs are taken up through both passive diffusion and energy-dependent endocytosis pathways; (III) prolonged exposure enhances MNP uptake by altering gene expression related to cell junctions, endocytosis, and inflammation; and (IV) intestinal inflammation, such as in inflammatory bowel disease (IBD), increases MNP translocation by enhancing intestinal permeability, which further promotes biodistribution. To achieve these objectives, the study is organized into two specific aims: Aim 1: Synthesize and characterize environmentally relevant “tracer” MNPs (Au Core-Plastic Shell) for use in toxicological studies. These physicochemically characterized MNPs will be subjected to weathering/aging processes to simulate environmental conditions, and will enable MNP quantification using ICP-MS. The characterization will focus on the physicochemical properties of MNPs, including size, polymer type, and surface chemistry. Aim 2: Investigate MNP translocation mechanisms and toxicity using advanced in vitro models. This will include a triculture model of the small intestinal epithelium and human Intestine-on-Chip (IOC) models derived from both healthy and IBD donor organoids. Simulated digestion will replicate real-world exposure conditions, and the effects of MNPs on intestinal toxicity, gene expression, and inflammatory response will be examined. In addition to providing state of the art, transdisciplinary training to a doctoral student, the findings from this research will provide critical data for assessing the risks of MNP ingestion, inform regulatory actions, and open new research avenues in toxicology and epidemiology for this emerging environmental pollutant.