Rutgers Biomedical And Health Sciences

NIH Research Projects · FY 2025 · 2023-09

Substance use disorder (SUD) treatment availability and use remain low despite an ongoing drug overdose epidemic in the United States. In 2019, 19.3 million non-institutionalized adults met the criteria for SUD, but only 2.6 million received specialty treatment services. People referred to SUD treatment through the criminal legal system are less likely to receive services (e.g., medication for opioid use disorder) than those who self-refer to specialty treatment. As a result, the criminal legal system may contribute to differences in SUD treatment need, use and outcomes in the community. Substantial knowledge gaps remain about how the criminal legal system, specifically county-level incarceration, affects community-level SUD treatment need, availability, use, and related outcomes. These gaps are exacerbated by the siloing of healthcare delivery system and criminal legal system data. To fill these gaps, we will link comprehensive multi-level data from counties in all 50 states from 2004-2023. We will quantify how county jail and prison incarceration rates are associated with: (Aim 1) community SUD treatment need (drug-related mortality rate, drug-related emergency department visit rate, SUD prevalence); (Aim 2) SUD treatment availability (number and types of available treatment services); and (Aim 3) SUD treatment use (self-reported, admission rates) and treatment outcomes (completion, retention) across communities and individuals. We hypothesize that greater county incarceration is associated with greater SUD treatment need (and vice versa), lower treatment availability, smaller increases in treatment use, and worse treatment outcomes. We anticipate that these relationships will have important spatial dependencies. Our hypothesized pathways and research process are grounded in theory. Our team, led by an Early-Stage Investigator, has expertise in substance use epidemiology and treatment, criminology, criminal legal systems, health policy and health systems, population health, biostatistics, and spatial methods. We will apply this expertise to study the criminal legal system, focusing on modifiable reform targets that can perpetuate and worsen SUD treatment-related outcomes over time. Our study addresses NIDA’s Notice of Special Interest (NOT-DA-19-037) calling for multi-level health services research on SUD treatment. By leveraging multi-level data sources and engaging with stakeholders, this innovative R01 examines how multiple systems converge to affect community health. We will incorporate experts and people with lived experience in the research process. Our multi-pronged dissemination plan will ensure that findings reach target audiences and inform health policies and programs that improve community-based SUD treatment-related outcomes.

NIH Research Projects · FY 2023 · 2023-09

Summary The age-induced decline in organ functions involves multiple cell intrinsic events. However, and since most physiological processes are orchestrated by extracellular environment, aging is also a consequence of progressive breakdown of extracellular milieu which proffers potential targets for anti-aging therapeutics. Taurine is a semi-essential micronutrient found in organisms across eukaryotic phyla. In mammalian cells, taurine is produced from cysteine by the action of cysteine sulfinate decarboxylase (Csad) and performs a variety of important functions. Taurine can also be obtained from extrinsic sources through a transporter (Slc6a6). Taurine supplementation to young wild-type mice improves, while congenital taurine deficiency due to the lack of SLC6A6, in humans and in mice, impairs functions of multiple organ systems known to be affected during aging. These evidences suggest that taurine may regulate processes associated with aging; however, the effect of taurine on healthspan and lifespan in aged animals, developmental versus postnatal origin, and the underlying mechanisms are unknown. Our preliminary results show that circulating and tissue levels of taurine decline with age in mice, monkeys, and humans. This led us to hypothesize that taurine deficiency is a driver of normative aging. Consistent with this hypothesis, once-daily oral administration of taurine to middle-aged WT mice significantly increases, without any noticeable side effects, in both females and males, the lifespan by 12% and 10%, respectively, and suppresses morbidity. The lifespan extending effect of taurine was also observed in worms suggesting that the effect of taurine transcends the eukaryotic evolutionary landscape to invertebrates. An unbiased association analysis of taurine levels with clinical variables in aged-humans shows that taurine levels associate with several degenerative diseases; and importantly physical exercise, which is known for its anti-aging effects, increases taurine levels in humans. Illustrating the biomedical relevance of above findings, daily oral feeding of taurine to aged-monkeys for 6 months significantly enhanced the functions of several organs. Mechanistically, we find that taurine regulation of healthy lifespan is associated with changes in hallmarks of aging, including a reduction in cellular senescence, increase in autophagy and proteostasis, suppression of mitochondrial dysfunction, and attenuation of inflammaging. In Aim 1, we will determine the degree to which short-term taurine supplementation at mid-life affects aging hallmarks and extends healthy lifespan through transient (3-, 6- or 12-month) and life-long taurine supplementation. In Aim 2, we will determine the effect of developmental versus postnatal taurine deficiency in regulating aging hallmarks, and healthy lifespan through inducible conditional ablation of Slc6a6. In Aim 3, we will begin to identify the contribution of aging hallmarks and upstream mechanisms through which taurine regulates healthy lifespan. Together, our studies are significant as they will establish taurine deficiency as a driver of aging, elucidate its developmental versus postnatal effects, and will identify the mechanisms through which taurine regulates normative aging.

NIH Research Projects · FY 2025 · 2023-09

Project Summary African-Americans/Blacks (AA/B) and Hispanics/Latinos (H/L) are vastly underrepresented in tobacco regulatory sciences research. Yet as their smoking persists, these groups bear the most significant burden of tobacco-related health diseases, including cancer. These disparities are due, in part, to the use of flavored tobacco products, like little filtered cigars and cigarillos (LCCs), and the tobacco industry’s aggressive promotion of LCCs to AA/B and H/L communities. An intended consequence of the anticipated flavor ban is the smoking reduction of flavored LCCs. However, the tobacco industry’s repackaging of their flavored tobacco products and their rhetoric about over-policing and discrimination against AA/B smokers threatens to disrupt the health equity impacts of the impending flavor ban. Critical gaps in the scientific evidence exist about the effects of exposure and receptivity to cigar product repackaging and socio-political rhetoric on AA/B and H/L young adults’ (YA) smoking behavior. Our proposed project seeks to address gaps and provide evidence to the FDA’s Impact, Marketing, and Behavioral domains by answering: “Do cigar product repackaging and rhetoric about over-policing and illicit cigar trade influence AA/B and H/L YA’s flavor ban perceptions and predict future LCC smoking behaviors among non-users and current users?

NIH Research Projects · FY 2025 · 2023-09

Abstract East Trenton, NJ is an environmental justice (EJ) community burdened by lead (Pb). Pb is a cumulative environmental toxicant that can affect multiple organ systems including the central nervous system. Current public health guidelines state there is no safe level of Pb exposure. This project’s priority is to reduce Pb exposure to residents. Partnering with three local community organizations, Isles Inc, East Trenton Collaborative, and New Jersey Future, community volunteers will conduct citizen science collecting soil samples from homes throughout the East Trenton neighborhood. Concurrently, Rutgers, ETC, and NJ Future will host community clinics to offer free blood Pb testing to concerned residents. While no resident will be turned away, a special emphasis will be placed on collecting blood samples from children. A home visit (minimum 100 homes) will be conducted in any home that tested above 200 ppm soil Pb (50% EPA residential soil Pb hazard level) or with a resident’s blood Pb level >0.5µg/dL. Drinking water, paint, soil, and house dust will be collected and analyzed for Pb isotope ratios and metal-to-metal ratios (e.g., Ti/Pb, Sb/Pb, Ga/Pb, etc.). Bayesian mixing models will be created using this tracer data to conduct source apportionment that will identify unique fingerprints for lead sources in blood and house dust. Home specific mitigation strategies will be developed using data from these mixing models that are specific to the unique sources of lead identified in the home environment. If a lead paint abatement is required, our community partner (Isles, Inc.) will conduct the lead paint abatement. Other mitigation strategies, (eg ground cover for exposed soil, entry way dust collecting mats to trap street dust) will also be recommended and a follow up visit to these 100 homes will be conducted 6 months post-mitigation to test the efficacy of the recommended mitigation strategies. During this visit, blood and house dust samples will be collected to determine if there was a decrease in exposure. Finally, dissemination of results will occur through town hall style community presentations and written reports will be provided to our community partners. This project is valuable because it will develop a playbook that can be used as an intervention model for other lead burdened communities on developing personalized abatement strategies available by adding source apportionment to the toolbox for exposure assessment.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Given their physiochemical properties, medications and dietary supplements often require active transport using solute carriers (SLC) and ATP-binding cassette (ABC) transporters to cross trophoblast barriers. These same transporters are also involved in the delivery of nutrients to the fetus and one unintentional consequence of drug therapy during pregnancy can be disruption of these shared systems. Therefore, understanding the interplay between SLC and ABC transporters in the placental disposition of drugs and nutrients is one key step to optimizing therapeutic interventions that improve perinatal healthcare. Our research team has championed the advancement of novel approaches to study SLC and ABC transporters in the placenta. To expand these efforts, we have created the Integrated Transporter Elucidation Center (InTEC) which leverages translational research expertise across 4 academic institutions. Our central hypothesis is that novel regulation and functions of placental transporters can be elucidated using integrated experimental, epidemiological, and modeling approaches. Together, data and models generated can predict the placental disposition of therapeutics and nutrients and their subsequent effects on fetal development. To accomplish this goal, we will 1) identify critical factors that regulate placental transporters using state-of-the-art quantitative targeted absolute proteomics and genetics in a US-based birth cohort; 2) develop a novel computational modeling framework that predicts maternal-fetal chemical disposition according to placental transporter functions and regulation; and 3) evaluate SLC and ABC transport in novel placenta-on-a-chip microphysiological systems. We will test nutrients, supplements, drugs, and toxicants as substrates and inhibitors of placental transporters. InTEC will enable rapid acceleration of placenta transporter research and establish best practices for transporter biology. Resources and datasets will be disseminated via our CIIPro webportal created in 2017. Unique training opportunities will be provided to early career scientists (undergraduate students, MS/MPH/PhD students, and postdoc fellows) and clinicians (obstetrics residents and fellows) at the intersections of pharmacology, computational biology, public health, maternal-fetal medicine, and biomedical engineering. Through innovative research and training, InTEC will lead to novel breakthroughs in the field of placental transport and ensure a well-trained workforce to improve maternal and perinatal health.

NIH Research Projects · FY 2026 · 2023-09

PROJECT DESCRIPTION The PI for this R00 proposal, Dr. Salman Qasim, is transitioning to a tenure-track faculty position in the Department of Neurosurgery at Rutgers Robert Wood Johnson Medical School. The original research proposed remains unaltered. Briefly, this project seeks to answer decision-making influences memory to leave a long-lasting impact on human behavior. Answering this question is critical to understanding how impaired decision making might lead to maladaptive memory outcomes, such as rumination on negative events, susceptibility to false memories, or memory loss. In recent years, the reinforcement learning (RL) framework has been particularly fruitful for describing impaired decision-making in psychiatric disorders as well as identifying computational mechanisms linking decision-making and memory. The overarching aim of this project is to identify the neurocomputational mechanisms that explain how the learning processes driving decision-making also influence subsequent memory. To do so, the R00 phase of the study will deploy computational and neurobiological approaches to study the contributions of model-based reinforcement learning to these distinct memory processes. Specifically, the results of the K99 project show how model-free RL signals such as prediction errors enhance memory, how this influence is weakened in a negative affective state, and how neural activity in the frontal cortex, hippocampus, and nonhippocampal medial temporal regions (such as amygdala) subserve the influence of model-free RL processes on memory performance. The PI obtained new training in computational modeling of reinforcement learning and decision-making that will enable the successful completion of the R00 research project: to study how model-based RL processes influence mnemonic behavior and neural activity.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Severe destructive behavior represents a comorbid condition of developmental disability for which risk increases with intellectual disability severity, communication deficits, and co-occurring autism spectrum disorder.1,2 Destructive behavior, such as self-injurious behavior and aggression, causes harm to the child and others and increases the risk for institutionalization, social isolation, physical restraint, medication overuse, service denial, and abuse.3 Clinicians have used functional analyses to identify the variables that reinforce destructive behavior and to develop effective, function-based treatments.4-7 Functional communication training (FCT) is an empirically supported, function-based treatment that decreases destructive behavior.8,9 Using FCT, the clinician teaches the child to use a functional communication response (FCR) to request the reinforcer maintaining destructive behavior, while placing destructive behavior on extinction.10-12 For example, if functional-analysis results showed that attention reinforced destructive behavior, the clinician would provide attention when the child used the FCR (“Play with me, please”) and would not provide attention for destructive behavior. Two important limitations of FCT are that (a) schedules of reinforcement maintaining the FCR must often be thinned gradually to levels that are practical for caregivers to implement consistently in the home and in the community,13-15 and (b) this necessary process of reinforcement schedule thinning regularly causes destructive behavior to increase following initially effective treatment, a form of treatment relapse called resurgence.16-19 The current project aims to improve these limitations of FCT by (a) hastening the process of reinforcement schedule thinning by removing unnecessary schedule-thinning steps using the results of a progressive interval assessment20-23 and (b) mitigating the resurgence of destructive behavior by providing stimuli that highly compete with the reinforcer maintaining destructive behavior.23-27 We will conduct a randomized controlled trial to evaluate the extent to which these two promising refinements to FCT improve the process of reinforcement schedule thinning, and an exploratory study will examine the interactive effects of these two approaches. This novel project has the potential to substantially improve standards of care guiding the treatment of severe destructive behavior and to improve the long-term outcomes for children and families afflicted by these debilitating behavior disorders.

NIH Research Projects · FY 2025 · 2023-09

SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with limited therapeutic options. About 95% PDAC patients harbor oncogenic mutant KRAS (KRAS*) that promotes pancreatic carcinogenesis and is required for PDAC maintenance. Given that KRAS* can be druggable now, therapy resistance occurs in several pre-clinical models and clinical trials, suggesting that therapy combination is required to achieve durable disease control. Targeting KRAS* results in enrichment of tumor associated macrophages (TAMs) in pancreatic, colon and lung cancer models, offering opportunities for chimeric antigen receptor (CAR) macrophage (Mφ) therapy and for Mφ-mediated cancer-specific delivery of pro-inflammatory cytokines. However, transplanted Mφs were prone to accumulate in liver, lung, and spleen despite that most of the remaining Mφs were localized in tumors, rising safety concerns that might be addressed by conditional gene expression systems. The hypothesis is that tumor-conditionally expressed cytokine armored CAR Mφs (ca-CAR-Ms) may synergize with KRAS* inhibitors (KRASi) to effectively suppress primary tumor growth, metastasis, and tumor recurrence and to prolong survival in PDAC spontaneous metastasis mouse models. A successful outcome of proposed study will generate the first ca-CAR-M therapy for PDAC treatment, pave the way for clinical trials in KRAS* PDAC patients and provide applicable methods to develop ca-CAR-Ms for other Mφ-enriched cancers. Aim 1. Optimize cell culture and engineering platforms for adoptive macrophage therapy. Primary Mφs are non-proliferative in vitro, and accumulation of donor Mφs in healthy organs is a latent safety risk. Aim 1a will enable in vitro expansion of Mφs by genetic or chemical screening of Mφ self-renewal regulators. Aim 1b will limit off-tumor activity of donor Mφs by employing dual oxygen-sensing switch and identifying TAM-specific genes versus tissue-resident Mφs, whose promoter/enhancers will be used for tumor-specific gene expression. Aim 2. Design CAR Mφs to target PDAC. The comprehensive CAR optimization for effective antigen-specific activation of phagocytosis and cytotoxicity in Mφs is lacking. Aim 2a will design and optimize constituent protein domains of CAR to direct Mφ activities against PDAC. Aim 2b will determine the tumoricidal effect of CAR-Ms as an adjuvant therapy of KRASi in PDAC models. Aim 2c will dissect mechanisms how CAR activation reprograms Mφ transcription, secretion, and pathway transduction to elicit tumoricidal effect. Aim 3. Engineer conditionally armored Mφs to trigger tumoricidal immunity. Mφs are tumor-homing, so delivery of pro-inflammatory cytokines by Mφs may reduce systemic toxicity while elicit strong anti-tumor immune response. Aim 3a will develop safe and effective cytokine armored Mφ therapy by cytokine screening and employing conditional transgene expression system. Aim 3b will assess tumoricidal activity of Mφs engineered by the optimal CAR construct, the top cytokine candidate or both as an adjuvant therapy of KRASi in various PDAC models. Aim 3c will delineate the role of cytokine armored Mφs in the tumor microenvironment remodeling by single cell RNA sequencing and immunophenotyping.

NIH Research Projects · FY 2026 · 2023-09

Project Summary The brain is a critical mediator of energy homeostasis, and neurocircuit dysfunction is thought to underlie obesity pathogenesis. Within the brain, the lateral hypothalamic area (LHA) exerts control over feeding behavior and body weight. Because of its considerable molecular and functional complexity, the role of LHA neurons in the development of diet-induced obesity (DIO) is still poorly understood. Addressing the LHA mechanisms governing feeding behavior and how they are remodeled during DIO will help to develop more targeted therapeutic interventions for obesity. Our overarching goal is to gain a mechanistic understanding of LHA neuronal dysfunction in DIO. Our previous work has demonstrated that the two most abundant cell types in the LHA— glutamatergic (LHAGlut) and GABAergic (LHAGABA) neurons—are transcriptionally remodeled by DIO. LHAGlut and LHAGABA neurons functionally oppose one another: LHAGlut neurons suppress feeding and reduce body weight, whereas LHAGABA neurons promote feeding and increase body weight. Our preliminary data confirm that LHAGlut and LHAGABA neurons show opposing changes in activity during acute manipulations of energy state and exhibit opponent transcriptional changes during DIO. These results highlight a potential role for LHA neuron dysfunction as a cause for overeating and DIO. However, the mechanisms underlying LHAGlut and LHAGABA neuron dysfunction in DIO are unknown. One factor that influences energy homeostasis, feeding behavior, and LHA activity is glucose. We therefore hypothesize that alterations in responsivity to glucose contribute to LHAGlut and LHAGABA neuron dysfunction in acute and chronic overnutrition and that restoration of LHA neuron activity can reverse the metabolic and behavioral impairments observed in DIO. To test this, we will determine the temporal dynamics of LHAGlut and LHAGABA neuron remodeling in DIO using longitudinal multiphoton in vivo imaging and electrophysiology. We will then test the hypothesis that glucose changes the activity of LHAGlut and LHAGABA neurons in vivo after acute and chronic overfeeding. Finally, we will test the hypothesis that restoration of LHAGlut and LHAGABA neuron activity can reverse the adverse consequences of chronic overnutrition. The results of this project will advance our conceptual understanding of the brain's involvement in DIO and identify novel therapeutic targets for the treatment of eating disorders and obesity.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Early environmental exposures are strongly implicated in the development of later diseases. The early life microbiome provides a developmental context for understanding health and disease across the life course. In the modern era, mothers and children routinely encounter microbiome perturbing exposures including cesarean section, infant formula, and antibiotics during pregnancy and in the child's first year after birth. Compelling basic science and epidemiological research from our group and others shows that perturbation of the pre-conception, prenatal, and early childhood microbiome contributes to adverse health outcomes. These connections are particularly strong for upper and lower airway health. Population-based studies document associations between asthma and early antibiotic exposure, and children with asthma have distinct microbiome signatures from unaffected children. Complementary mouse models show a causal association between perturbed microbiota and airway disease. However, key knowledge gaps remain. First, existing studies lack diversity and are often underpowered to evaluate the extent to which microbiome-perturbing exposures such as medication use, cesarean section, and infant formula underlie racial/ethnic disparities in outcomes such as the higher prevalence of asthma in Black and Hispanic children compared to White children. Second, few studies have examined the microbiome across critical time windows (preconception, pregnancy, delivery, infancy, and early childhood). ECHO provides a unique opportunity to address these gaps and study the developmental role of the early life microbiome in later health in a large, diverse U.S. cohort. We will recruit 500 pregnant people and their resulting offspring from Middlesex County, NJ, one of the most diverse counties in the U.S., into the national ECHO cohort. Our proposed scientific focus is on the early life microbiome and exposure to microbiome-perturbing exposures (cesarean section, infant formula, and medication use) in relation to upper and lower airway health. Our specific aims are to: (1) Characterize social determinants and racial/ethnic disparities in common microbiome-perturbing exposures during critical early life periods in the ECHO-wide cohort and evaluate associations with longitudinal microbiome structures in mothers and children; (2) Estimate associations between microbiome-perturbing exposures and child outcomes, with a focus on upper and lower airway health; (3) Recruit 500 pregnant participants reflecting the unique diversity of Middlesex County, NJ; and (4) (Exploratory) Examine the extent to which maternal microbiome perturbation in the 12 months before conception is associated with adverse upper and lower airway outcomes in children. The addition of NJ contributes unique diversity to the ECHO consortium. In turn, our team's ECHO-wide research at a national scale will yield knowledge that informs clinical and public health interventions that promote a “healthy” microbiome and improve child health.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Peri-implantitis is a prevalent, destructive, inflammatory disease that leads to loss of jawbone around dental implants and impairments in oral health-related quality of life. It poses a public health concern because bone loss progresses at a rapid rate and does not respond therapeutically to conventional periodontal antibacterial therapies. Multiple human studies have firmly established that implant hygiene and tribocorrosion generate implant degradation products, such as titanium microparticles, which are associated with inflammation in a large fraction of peri-implantitis cases, i.e., Titanium (Ti)-mediated peri-implantitis. While it is well documented that titanium microparticles alter peri-implant immune surveillance primarily by inducing oxidative stress, the effects that these changes have on the peri-implant microbiome have not been adequately investigated. The proposed research aims to investigate the genetic mechanisms employed by Veillonella parvula, a bridging microorganism in oral biofilms, to survive and cross-protect oral pathogens in response to environmental oxidative stress. Our preliminary studies demonstrated that increased free titanium levels in peri-implant plaque are associated with a significant reduction in the biodiversity of the peri-implant biofilms that is coupled with the overgrowth of V. parvula. Strong preliminary data point to an antioxidant catalase enzyme encoded by the katA gene as being a key survival system that enables V. parvula’s survival while most peri-implant commensal bacteria are depleted by Titanium-mediated oxidative burst. Importantly, Veillonella demonstrates widespread mutualism with oral pathogens, such as P. gingivalis and F. nucleatum and its catalase protects the latter from oxidative damage suggesting a community-level regulatory role. In this project, we will determine (i) the exact mechanisms used by V. parvula to survive oxidative stress, (ii) the role of katA and other key antioxidant enzymes in modulating biofilm oxidative tolerance, and (iii) the ability of oral pathogens to leverage Veillonella’s katA to colonize and survive in the oral mucosa soft tissue barrier during Ti- mediated inflammation. The long-term goal of this work is to identify the drivers of microbiome dysbiosis in peri-implantitis and to develop efficacious antimicrobial strategies for the management of peri-implant diseases. The objective of the proposed work is to assess the hypothesis that survival mechanisms of commensal Veillonella spp., which enable their overgrowth in this niche are leveraged by oral pathogens to colonize peri-implant microbial communities and lead to clinical disease. The proposed objective will be completed in two main Aims: 1) to identify how titanium-mediated inflammation promotes V. parvula overgrowth, and 2) to determine the extent to which V. parvula alters polymicrobial infection course in vivo. These findings will provide important insights in the role of oral commensal bacteria in modulating microbiome dysbiosis and will introduce novel therapeutic targets of peri-implantitis treatments.

NIH Research Projects · FY 2025 · 2023-09

Abstract/Summary Among the Epstein-Barr virus associated cancers is post-transplant lymphoproliferative disease (PTLD), a rare but major complication of pediatric solid organ transplants (SOT). Many children are EBV-seronegative at time of SOT, leading to primary EBV infection from the allograft under intense immunosuppression, and a higher chance of a chronic high viral load (CHVL) state or PTLD. Longitudinal peripheral blood EBV DNA nucleic acid testing (NAT) has not improved the individual prediction of PTLD occurrence, likely due to variable SOT recipient immune responses. Further, these patients receive clinical interventions for EBV DNAemia, with incomplete responses for unknown reasons. Our team of SOT, infectious disease and immunology professionals will bring new and complimentary expertise to close these knowledge gaps. We will perform longitudinal T and NK cell immune function assays in conjunction with local and central EBV and anellovirus NAT in 1390 samples across 5 time points in the first year after 278 SOT (kidney, liver, heart, lung or intestine) at 3 major children's hospitals. We will accomplish the following Specific Aims, comparing thoracic and abdominal SOT recipients with primary EBV infection or CHVL state: 1. Assess the prospective phenotypic and functional features of T cell “exhaustion” and correlate with EBV infection outcomes and NK cell profile. Hypothesis: SOT recipients' that develop CHVL state display distinct phenotypic memory differentiation and exhausted CD8+ and CD4+ T cell profiles that are regulated by distinct inflammatory circuits. We will accomplish this aim by performing multi- spectral flow cytometry to characterize T cell phenotype and function, as well as Meso Scale Discovery platform to assess distinct viral control-relevant plasma cytokines/chemokines, during the phases of initial replication, expansion, progression, CHVL or recovery states. 2. To prospectively define the number, phenotype, and functional status of NK cells, and correlate with EBV infection outcomes. Hypothesis: NK cell activation will coincide with primary infection, and will correlate positively with clearance vs. negatively with persistent EBV replication. NK cell dysfunction will develop in patients with CHVL, who are at highest risk of PTLD. We will leverage our established multi-spectral flow cytometry panel and analyze patients with primary EBV infection after SOT and answer questions related to the activation status, NK receptor repertoire, and functional capacity. 3. Determine the association of peripheral blood torquetenovirus (TTV) DNA loads to EBV outcomes, T and NK cell profiles. Hypothesis: TTV loads reduce with clinical reductions in immunosuppression and predict EBV clearance. We will accomplish this aim using longitudinal whole blood NAT assays for both viruses at common time points, performed centrally to minimize lab variability. By study end, we will know the T and NK immune responses to EBV across multiple clinical situations. We expect to find key immune mechanisms that will predict poor or delayed EBV clearance despite clinical interventions, which may lead to new translational immunotherapy approaches to prevent PTLD, or inform EBV oncogenesis in other populations.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is a spectrum of conditions characterized by lipid accumulation in the liver known as steatosis. Approximately 25% of the US population have NAFLD and approximately 30% of that population suffer from non-alcoholic steatohepatitis (NASH). NASH is the more severe and progressive form of NAFL that is characterized by liver steatosis, hepatocellular ballooning, inflammation, and fibrosis. NASH is also the leading indicator for liver transplantation in the US. Other than lifestyle changes, there is no current FDA- approved therapeutic for NASH; however, one emerging target is the Farnesoid X Receptor (FXR). FXR is a ligand activated transcription factor highly expressed in numerous tissues such as the liver and intestine and is a major regulator in bile acid (BA) homeostasis. BAs have been implicated in NASH development and progression and FXR deficiency in male mice leads to more severe NASH development. Because FXR negatively regulates BA production, synthetic ligands that are whole-body FXR agonists have been developed to treat NASH. Although beneficial, these whole-body modulators contribute to unfavorable side effects such as cholesterol homeostasis imbalance, thereby explaining the importance of FXR tissue-specific activation in the development of novel therapeutics for NASH to negate any potential harmful consequences. Our preliminary data suggests that deletion of FXR expressed in the livers of mice is more critical in NASH development compared to the deletion of FXR expressed in the small intestine. The underlying mechanisms leading to these differences are not well elucidated. Understanding these mechanisms contributing to FXR functionality in a tissue-specific and cell-specific manner will allow scientists to develop safe, targeted, and efficacious therapies for NASH. In addition to determining which organ or cell type is most appropriate to target for the synthesis of pharmacological interventions for NASH, deciding whether FXR activation or inactivation is most beneficial in the treatment of NASH needs to be determined, particularly pertaining to FXR in the gut. Conflicting studies show that both intestinal FXR agonism and antagonism are beneficial in the treatment of NASH. Aim 1 will determine the tissue-specific role of the the farnesoid X receptor in NASH development in mice. Aim 2 will determine the effects of ursodeoxycholic acid, an FXR antagonist, on NASH prevention in mice. Through the completion of the research and training described in this F31 Fellowship, the Principal Investigator will be trained in basic biomedical research and biological processes contributing to metabolic disease development and prevention, focusing on NASH. The Principal Investigator will be prepared to conduct independent research and enhance the diversity of the scientific workforce, and to assist in improving the health and quality of life of individuals suffering from this chronic liver disease, which is in line with the mission and vision of the National Institute of Diabetes and Digestive and Kidney Diseases.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT In humans, fetal growth restriction (FGR) and impaired placental development are associated with infant morbidity and mortality and susceptibility to adulthood diseases. In pregnant animals, inhalation of particles alters the functionality of the uteroplacental vasculature, leading to impaired placental and fetal growth. Particulate matter (PM) can target the uteroplacental vasculature in multiple ways. One way by which particles can disrupt the uteroplacental vasculature is by impairing vasodilation. During pregnancy, uterine vessels must be sensitive to vasodilation mediators to meet the dynamic needs of the placenta and fetus. Central to this vasoreactivity is the endothelial cell that translates signals from the blood to the vascular smooth muscle cells, leading to vessel dilation or constriction. Additionally, the placenta is a critical organ for the diffusion of oxygen and transport of nutrients to the developing fetus. PM can impair development of the placental vasculature that allows for maternal-fetal exchange and decrease the ratio of placental-to-fetal tissue, known as placental efficiency. Our laboratory recently showed that plastic particles can translocate through the placenta to the fetus after pulmonary exposure, suggesting that the particles directly interact with the uteroplacental vasculature. The environmental burden of plastics is exponentially increasing. Micro’ nanoplastics (MNPs) represent a ubiquitous exposure concern for the general population and for vulnerable groups, such as pregnant women, it is important to elucidate how MNP inhalation may affect fetal development. These particles are generated and suspended in the air by the combustion of bulk plastic or through slower processes like mechanical degradation where a bulk plastic fragments into small pieces in the microparticle (>100 nm) and nanoparticle (<100 nm) size range. Our preliminary data demonstrates that MNP inhalation in virgin female rats disrupts uterine vascular reactivity. Furthermore, using a pregnancy model of MNP inhalation throughout gestation, we observed FGR, increased placental weight, and decreased placental efficiency suggesting the placenta is a target organ of MNPs in rats. Therefore, the central hypothesis of this proposal is that maternal inhalation of MNP throughout gestation decreases placental efficiency by impairing uterine vasodilation and disrupting development of the placental vasculature in rats. The aims in this proposal will investigate the mechanisms by which repeated maternal MNP inhalation dysregulates the uterine vasculature and placental development, thus contributing to FGR. Aim 1 will identify mechanisms of impaired uterine vascular reactivity and how endothelial cell function is altered after maternal MNP exposure. Aim 2 will determine how maternal MNP inhalation modifies development of the placental vasculature using histopathological analyses and immunohistochemistry. This research will identify mechanisms of MNP induced FGR and present potential targets for therapeutic intervention. By completing the proposed research, courses, and training the Principal Investigator will be trained independently conduct state- of-the-art experimental techniques and carry out cardiovascular and reproductive toxicological research.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY: Diversity improves the ability to conduct research in all fields, but is especially crucial for biomedical research, essential to our efforts to improve the health of the nation. Despite decades of sustained effort, fewer than 2 percent of NIH primary investigators are Black, lower than the percentage of Black faculty at medical schools and much lower than the general population. The same holds true for Hispanics and other underrepresented groups (URGs). New, inventive solutions are thus urgently needed to promote the advancement of biomedical URGs trainees. Here we propose individualized professional coaching as a scalable and effective intervention. Coaching is a practice where a professionally trained coach helps the coachee clarify aspirations, increase self-awareness, establish plans, take action to achieve goals, and overcome challenges. Coaching research in a number of different academic settings has demonstrated improved self-efficacy and mental health, which are needed for sustained academic success. However, professional coaching has never been rigorously tested as an intervention for biomedical Ph.D. students, which is a significant gap in knowledge. Using hypothesis-driven research, we will test the following hypothesis: Biomedical Ph.D. students who receive individualized academic coaching will experience improved short-term outcomes (e.g., self-efficacy, resilience, reduced anxiety and depression) and sustained positive effects (degree persistence, goal attainment, ease in career transitions, and tangible scholarly outputs) compared to their controls. An interdisciplinary team at Rutgers with deep expertise in biomedical Ph.D. education and training, diversity, equity, and inclusion (DEI), professional coaching, mental health, biostatistics, and rigorous mixed-methods educational research will test this hypothesis in the following three aims. For reproducibility, all experiments will be conducted at two institutions: Rutgers-New Brunswick (R-NB) and Rutgers-Newark (R-N). The experiments will be an academic year (AY)-long and utilize International Coaching Federation (ICF)-accredited coaches. URG and well-represented (WR) students will be randomly assigned to either control (no coaching) or experimental groups (coaching). In Aim 1, validated instruments will statistically measure short- and medium-term effects of professional coaching on goal attainment, self-efficacy and mental health (anxiety, depression, resilience). As a complementary approach, mixed methods will determine what gains occur, how they occur, and for what student populations they are most pronounced. Our hypothesis will be first tested at R-NB and then at R-N. In Aim 2, the coaching elements that lead to success will be defined including: i) dosage (frequency, duration) and ii) efficacy of Rutgers faculty/staff trained as ICF coaches. In Aim 3, long-term effects will be measured (e.g., time to degree, career transition, self- efficacy, and resilience). The proposed innovative research will have high impact by not only testing for the first time whether coaching is an efficacious and scalable intervention, but by also identifying the key elements needed for its implementation across institutions to address ongoing URG disparities in the workforce.

NIH Research Projects · FY 2025 · 2023-08

SUMMARY Neonatal brain injuries, hypoxia-ischemia (HI) brain injury is one of the leading causes of disability in children. Mitochondrial dysfunction due to activation of permeability transition pore (mPTP) has been implicated in cell death after HI insult but only in the mature brain. It has been proposed that mPTP is non-specific protons/ions leak across the inner mitochondrial membrane which dissipates proton motive force and renders mitochondria deficient or incapable of ATP production, often driving cellular death in the ischemic brain. However, the strategies to address mPTP in the model of HI brain injury in neonatal mice or rats were unsuccesful. Thus, an identical biophysical process, an activation of mPTP, triggered by similar HI stress contributes to the brain injury in the mature animals and may not be mechanistically significant in the immature brain. We have reasoned and found that biophysical and pharmacological properties of the mPTP activated during HI in neonates differ from that in adult animals. In neonates these mPTP are not cyclophilin D (CypD) dependent. This a) defines neonatal failure of the strategies which are neuroprotective in adults and b) require a different therapeutic approach. Aim 1. To determine if CypD-independent mML contributes to SEF and cellular injury during reperfusion. Aim 2. To determine the pharmacological regulation and structure of CypD- independent mitochondrial membrane leaks. Aim 3. To determine the role of CypD-dependent mPT in neonatal HI brain injury. Our work will provide the very first direct evidence for pathogenic role of mitochondrial permeabilization in neonatal HI brain injury models. This will allow us to better understand its regulation and structure function relationship and help to develop highly efficient strategies of brain protection against hypoxic ischemic stress by direct targeting of the ion-conducting parts of the mPTP.

NIH Research Projects · FY 2025 · 2023-08

Overall ABSTRACT The Rutgers University Regional Biocontainment Laboratory (RBL) serves as a central facility to perform biosafety level three (BSL3) therapeutic, pathogenesis, and diagnostic research on high threat biological agents with a focus on Mycobacterium tuberculosis and SARS-CoV-2, as well as other category A, B, and C pathogens. The RBL serves academic and commercial entities within Rutgers University, the Northeast United States and nationally, while also engaging globally with companies and academic institutions through collaborations and research contracts. This proposal will provide support that enhances the RBL’s ability to fulfill its research and biothreat response/pandemic preparedness missions while also supporting an expanding faculty/staff. We propose to accomplish these goals by improving the RBL facilities, support services, BSL3 practice development and implementation and special services offerings though the execution of three aims: Aim 1. Establish a Facility management, maintenance and operations (FMMO) core. Aim 2. Establish a BSL-3 Practices core (Practice core). Aim 3. Establish a biocontainment research support service core devoted to developing animal models of BSL3 pathogens and associated support services (Animal models and related services, or AMRS core). The FMMO core will provide BSL3 and ABSL3 services, management and oversight, for routine animal husbandry, microbiology and virology services in support of investigators grant funded research projects while ensuring efficient operations and maintenance of the BSL3 facilities and providing trained staff to support the BSL3 building systems and equipment. The Practice core will develop and maintain standard operating procedures and training for research in the RBL BSL3 laboratories including best practices, emergency response, waste management, shipping, husbandry, select agent-specific practices and inventory. It will also develop and conduct biosecurity and disaster drills and liaise with other BSL3 laboratories within the RBL network as well as local, state and federal health agencies to coordinate operations and plan for joint responses to new infectious disease threats. The AMRS core will develop critical animal models including those of SARS-CoV2 and highly pathogenic influenza virus transmission, COVID-19 PASC, pulmonary impairment after TB (PIAT), and drug treatment models, and then support grant funded investigators in the performance of these models along with the advanced instrumentation needed to analyze these infected models and their tissues/cells in a BSL3 environment. Together, these three cores will significantly enhance the near- and long-term abilities of the RBL to address critical biothreats and emerging infectious diseases requiring study in a BSL3 laboratory setting, while also increasing our capacity to respond to the next public health emergency or pandemic.

NIH Research Projects · FY 2025 · 2023-08

ABSTRACT Although therapeutic use of cannabis is increasing, findings are mixed regarding therapeutic effects of cannabis for certain conditions, such as anxiety. Further, acute cannabis effects could adversely impact psychomotor performance (e.g., slowed reaction time), with subsequent negative effects on daily activities (e.g., work performance, driving skills). Low burden methods to monitor acute cannabis effects through sensors in personal smartphones could ultimately help reduce cannabis's acute negative effects on psychomotor performance by helping to raise a person's awareness of cannabis-related impairment. Toward this goal, this R01 will collaborate with individuals who use medical cannabis (MC) in monitoring, with their smartphone, acute therapeutic and adverse effects of cannabis use. Individuals who use MC commonly report cannabis use to relieve chronic pain and/or anxiety, the two conditions of interest for this R01. Smartphone will be used to conduct symptom monitoring of acute cannabis effects on chronic pain and anxiety using Ecological Momentary Assessment (EMA). Phone sensor data will be used to examine acute cannabis effects on psychomotor performance. These fine-grained smartphone "micro" data (e.g., momentary-level) will be combined with longer-term follow-up over 1-year, to examine the impact of cannabis use at a more "macro" level (e.g., over months), because cannabis effects (e.g., on anxiety) at "micro" and "macro" time scales may differ. This R01 will recruit individuals who report therapeutic use of cannabis, with chronic pain and/or anxiety as the primary reasons for MC use (N=400, age >18; 50% female). Participants complete lab assessments at baseline, 3-, 6-, and 12-months in a repeated measures design. Saliva sample for THC and CBD level will be done at baseline, 3-, 6-, and 12-months. Each assessment (baseline, 3-, 6-, 12-months) is followed by 14-day daily EMA and phone sensor data collection. Daily EMA (3x/day) and self-initiated EMA of cannabis use (medical, non-medical) will be used. Phone sensor data include, for example, keyboard use (not message content), and accelerometer (e.g., to detect activity level). Study aim 1 will examine links between acute cannabis use and effects (EMA report), psychomotor performance (phone sensor data), and self-reported daily cognitive functioning (e.g., react slowly to things). Study aim 2 will test links, over 1-year, of longer-term effects of cannabis use, computerized measures of psychomotor performance, and self-report of cannabis-related consequences. For each aim, gender differences in cannabis's short and longer term effects will be explored. The combination of fine-grained subjective (EMA) and objective (phone sensor) data, collected at micro (EMA) and macro time scales over 1-year, will help resolve mixed findings on possible cannabis-related therapeutic benefit, acute risks, and longer-term outcomes (e.g., on psychomotor performance). In line with NIDA priorities, this R01's novel combination of symptom monitoring methods (EMA, phone sensor data), and "micro" and "macro" data, will guide development of mHealth interventions that reduce risk for cannabis-related harm.

NIH Research Projects · FY 2025 · 2023-08

ABSTRACT Asian and Pacific Americans (APAs) have undergone the greatest growth among all racial/ethnic groups in the U.S. between 2000 and 2020. In the New York City/New Jersey (NYC/NJ) area, older (65+) Asian Indian and Chinese American populations have increased by 73% and 74% over the past ten years. While claims-based studies in the U.S. have previously suggested lower prevalence of Alzheimer’s disease (AD) and related dementias (ADRD) in older APAs, this finding may have resulted from underdiagnosis associated with not having culturally and linguistically appropriate tools, clinicians, or systems. Older APAs with AD/ADRD in the U.S. thus face both the problem of under-diagnosis and under-provision of care as a whole, even as great disparities exist within and between APA subgroups. What’s more, the COVID-19 pandemic and the associated anti-Asian discrimination brought greater social isolation to older Chinese and non-Chinese APA adults over the past three years than other groups. These factors together formed the foundation of the Resource Center for Alzheimer’s and Dementia Research in Asian and Pacific Americans (RCASIA) with missions of 1) increasing scientists underrepresented in AD/ADRD-related Behavioral, Social, and Economic Research biomedical research through innovative models of mentoring and community interaction; 2) advancing the rigor and impact of AD/ADRD pilot studies in older APAs through Common Data Elements and data-sharing; 3) serving as a national resource for linguistically/culturally tested and validated tools to assess cognition, function, and AD/ADRD care in APA populations. Focusing on the theme of People, Culture, Place, Time, RCASIA will leverage strong institutional support and relationships to solicit pilot applications from Early Stage Investigators (ESIs). We will actively engage and encourage applications from ESIs at NYC/NJ-based Minority Serving Institutions through pre-application RCASIA internships and partnership commitments from large funded studies prospectively recruiting disaggregated older APAs. Scientist mentoring will occur in the Research Education Component (co-led by a returning REC Core Lead and a newly recruited yet established AD/ADRD Education/Psychosocial Core Lead) involving mentoring/method-based Pods and ethnicity-based Teams. REC will be supported by the Leadership & Administrative Core, the Measurement & Analytical Core, and Community Liaison & Recruitment Core in selecting each year’s class of RCASIA Scientists, enhancing multi-generational method and career development in Pods, conducting transdisciplinary engagement with Community & Lived Advisors in Teams, and evaluating the outcomes of Scientists, effectiveness of the Pod/Team model, impact of Common Data Elements and data sharing, and long-term relationships between RCASIA and funded Scientists. Returning and new faculty’s commitment to diversity, equity, inclusion, and access and APA brain health will contribute to RCASIA’s goal of becoming the epicenter for AD/ADRD-related Behavioral, Social, and Economic Research in older APA populations.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT Individuals with Down syndrome (DS) are at higher risk for developing Alzheimer’s disease (AD) compared to the general population. As such, they are considered an ideal target population for anti-AD therapy trials; however, there is no reliable measure for predicting dementia onset in this population. Intraindividual cognitive variability (IICV), a measure of variability in neuropsychological test performance within a person at a single timepoint, is a novel, low-cost, non-invasive biomarker of neurodegeneration and early dementia for the general population. However, IICV has not been investigated in adults with DS. Therefore, the current proposal will fill this knowledge gap by characterizing the associations between IICV, AD biomarkers, and dementia in adults with DS. Aims 1 and 2 of this proposal use data from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) study, which is currently composed of cognitive and biomarker data collected at two different timepoints (baseline and 18 months), to calculate IICV measures for memory, executive function and processing speed, visuospatial construction, and multidomain cognition in 300 adults with DS. Using the longitudinal ABC- DS data, we will first examine whether IICV is associated with AD plasma biomarkers (β-amyloid 42/40, p- tau217, and NfL) and/or AD-related pathology (Aβ-PET and tau-PET) (K99, Aim 1). We will also examine whether IICV is associated with the clinical presentation of dementia and cognitive decline (K99, Aim 2). We expect our analyses to show that IICV is positively associated with AD-related biomarkers and pathology, and that IICV at baseline is associated with a follow-up diagnosis of dementia as well as cognitive decline from baseline to follow-up. These data will be critical for optimizing the design of a new cohort study of adults with DS that will test the outcome measures from Aims 1 and 2 in a new, more diverse, cross-cultural cohort of adults with DS from Washington State and São Paulo, Brazil, and include comparisons with a control group of individuals with autosomal dominant AD, due to its similarity with DS in early striatal amyloid- β deposition (R00, Aim 3). To complete these aims, we have developed a comprehensive, mentored training plan for me to (1) gain expertise in the relationship between neuropsychology, plasma biomarkers and neuroimaging; (2) broaden my knowledge of the similarities and differences between autosomal dominant AD and AD in DS; (3) explore cross-cultural similarities and differences in AD risk; and (4) develop advanced statistical skills. The data and training obtained in the K99 phase will lead to the successful implementation of a high-quality, international research program focused on IICV and AD biomarkers in DS. Findings have great potential to be used with the DS population worldwide, increasing the chances of early interventions and inclusion in anti-AD trials. The intense training in the K99 and the support of mentors with extensive expertise in all areas of the proposal, will provide the foundation for an independent scientific career on cross-cultural AD risk prediction in DS and other high-risk populations.

NIH Research Projects · FY 2024 · 2023-08

Rates of perinatal HIV transmission have fallen substantially due to increased access to antiretroviral therapy during pregnancy and breastfeeding. However, this has led to a growing population of infants who are HIV- exposed but uninfected (iHEU). iHEU display heightened inflammation, immune activation and immune exhaustion potentially driven by their altered gut microbiota. HIV exposure has also been linked to impaired growth (stunting) in infants. Multiple studies have shown evidence of stunting in iHEU compared to HIV unexposed infants (iHU). In addition, malnutrition studies have linked chronic intestinal inflammation, which also associated with gut microbiota alteration, in infants to impaired growth. The mechanism(s) behind impaired growth in iHEU are not understood. It is plausible that heightened intestinal inflammation in iHEU may associate with stunting. However, whether the gut microbiota in iHEU causes impaired growth has not been formally tested. Beyond growth, the gut microbiota impacts immune development. Specifically, microbiota composition early in life imprint lasting immunological consequences. iHEU display high infectious morbidity including to enteric pathogens. For example, studies have shown that iHEU exhibit high prevalence of enteropathogenic Escherichia coli (EPEC) and Cryptosporidium spp compared to unexposed counterparts. The gut microbiota has been shown to protect against enteric pathogens via various mechanisms including colonization resistance and alteration of mucosal immunity. Whether gut microbiota in iHEU enhance susceptibility to enteric pathogens is unknown. Human studies are based on correlations which limit ability to infer causation. We will utilize a germ-free neonatal mouse model to investigate the causal role of the early stool microbiota in iHEU in driving these clinical phenotypes. In addition, we will use a neonatal mouse model of EPEC to test causality between stool microbiota and immunity to enteric pathogens. We hypothesize that the gut microbiota of iHEU early in life causes inflammation, poor growth and impairs immunity to enteric pathogens. We propose to test this hypothesis with the following specific aims. Aim 1: To investigate whether the early life gut microbiota of iHEU causes intestinal and systemic inflammation and impaired linear growth during infancy. Aim 2: To investigate whether the early life gut microbiota of iHEU impairs immunity to enteric pathogens

NIH Research Projects · FY 2025 · 2023-08

Abstract The immunometabolism of tuberculosis (TB) offers new opportunities for controlling this deadly infectious disease. We and others have characterized the immunometabolic changes in multiple animal models of TB and found that metabolic remodeling to the HIF-1-mediated Warburg effect is a general response to infection by Mycobacterium tuberculosis, the causative agent of TB. Recently, using multiple approaches that include metabolomics and transcriptomic profiling, we identified novel core metabolic pathways that are found in both Mtb-infected M1-like macrophages and in mouse lungs. These include glutaminolysis and one-carbon metabolism. One-carbon metabolism catabolizes the transfer of serine-derived one-carbon (1C) units to generate methyl-tetrahydrofolate (THF) intermediates that are then utilized for nucleotide synthesis and for methylation reactions through the methionine cycle. One-carbon metabolism is also involved in redox balancing through the generation of NADH/NADPH and of glycine and cysteine for glutathione (GSH) synthesis. We also found that inhibition of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) leads to diminished M1-like polarization that includes dysregulated mitochondrial function and dampened mTORC1/ATF4 signaling in M1- like macrophages. MTHFD2 is a key mitochondrial enzyme of one-carbon metabolism that is encoded by Mthfd2, which is highly induced in Mtb infected M-like macrophages and mouse lungs. Based on these observations, we hypothesize that mitochondrial MTHFD2-mediated, one-carbon metabolism contributes to metabolic remodeling programs of activating immune cells by generating 1C units for nucleotide synthesis and methylation reactions, as well as reducing equivalents and GSH for redox homeostasis. Since TB is often associated with a deficiency of folic acid, the precursor of the 1C carrier THF, we also hypothesize that folic acid deficiency during Mtb infection dampens one-carbon metabolism, leading to diminished activation, differentiation, and effector function of host immune cells. Moreover, since elevated MTHFD2 in vivo is associated with inflammatory disease severity, we further hypothesize that prolonged and elevated expression of one-carbon metabolism contributes to lung pathology at the chronic stage of Mtb infection. To test our hypothesis, in Aim 1, we will delineate how MTHFD2- mediated, one-carbon metabolism regulates immunometabolic properties of M1-like macrophages, mitochondrial biology, serine metabolic pathways, and the mechanism of Mthfd2 upregulation. In Aim 2, we will generate conditional KO mouse strains lacking Mthfd2 in myeloid cells and T cell lineage to delineate the impact of Mthfd2 deficiency on disease progression and immunometabolic properties of immune cells and/or subsets. With Aim 3, we will use a susceptible mouse model of TB to evaluate the effects of folic acid dietary intake on the expression of host immunity to control Mtb infection. We will also define the therapeutic role of inhibitors targeting one-carbon metabolism during anti-TB treatment at chronic stages of the infection. Our study is expected to advance the development of urgently needed host-directed therapies (HDTs) to enhance the ability of immune cells to clear Mtb infection and/or to prevent the development of pathology.

NIH Research Projects · FY 2025 · 2023-08

Project Summary Our objective in this new R01 proposal is to delineate the impact of a spouse’s substance use and psychiatric disorders on their partner’s alcohol use disorder (AUD) onset, remission, and relapse during marriage within a genetically informative framework. To date, efforts to understand spousal influences on alcohol outcomes have largely focused on alcohol-specific contagion models, whereby alcohol use behaviors in one partner are socially transmitted to the other. Yet, this prior focus alcohol-specific contagion is restrictive in view of epidemiological evidence that spouses of AUD-affected individuals also tend to suffer from other common disorders, including major depressive disorder, generalized anxiety disorder, other drug abuse/dependence, ADHD, and antisocial personality disorder. We build on these epidemiological findings to clarify the nature of the associations between these other forms of spousal substance use and psychiatric disorders and key alcohol outcomes including AUD onset, remission, and relapse. We do this within a genetically informative framework that also recognizes the potential contributions of a spouse’s genetic propensity for a disorder even in the absence of a diagnosis (i.e., social genetic effects), as well as how the focal individual’s genotype may differentially sensitize him/her to a spouse’s disorder (i.e., gene-environment interaction effects). Relevant phenotypic and genotypic data for this secondary data analysis project come from spousal dyads (N = 1,688 dyads) collected as part of the NIAAA-funded Collaborative Study on the Genetics of Alcoholism (COGA). Our specific aims are to: (1) Delineate the temporal dynamics underlying associations between spousal substance use and psychiatric disorder diagnoses (inclusive of cannabis use disorder, other psychoactive drug use disorder, antisocial personal disorder, ADHD, nicotine dependence, major depressive disorder, and PTSD) and their partner’s AUD onset, remission, and relapse; (2) Identify whether a spouse’s genetic propensity for psychiatric disorders (above and beyond a diagnosis itself) is associated with their partner’s AUD onset, remission, and relapse; (3) Examine whether the focal individual’s genetic predisposition for alcohol problems predicts variability in their sensitivity to spousal substance use and psychiatric disorders; and (4) Evaluate whether the expected effects differ as a function of sex and parenthood. The results may have theoretical implications for expanding social stress models of AUD to include spousal substance use and psychiatric disorders, and in turn this knowledge is anticipated to have implications for couples and family systems-based preventive interventions for AUD. More broadly, this work will contribute to the collaborative research team’s long-term goal to elucidate how genetic factors and close relationship factors come together to influence the onset, persistence, and discontinuity of AUD.

NIH Research Projects · FY 2026 · 2023-08

Communities in the U.S. South continue to face disproportionate rates of HIV, particularly in areas identified by the Ending the HIV Epidemic in the U.S. (EHE) initiative. To respond to this, there is a critical need for scalable, community-driven interventions that enhance HIV-related health outcomes and address key barriers to health. In collaboration with a community-based organization with extensive experience in HIV service delivery, we developed NPOWER365, a multicomponent intervention that integrates individualized health education and motivation, fosters peer support, improves access to affirming healthcare services, and reduces barriers related to housing and economic stability. The intervention is guided by the Information-Motivation-Behavioral Skills model, social capital theory, and socioecological approaches to health. Pilot data suggest that NPOWER365 is feasible, well-accepted, and effective in supporting daily antiretroviral treatment (ART) adherence, as well as in reducing depressive symptoms, anxiety, and challenges with emotion regulation. The intervention is now ready for a full-scale evaluation using the RE-AIM framework, with a focus on its effectiveness, long-term use, and population reach. We propose a hybrid type 2 implementation-effectiveness trial, including a 6-month waitlist randomized controlled design with 350 participants, daily diary data collection, and longitudinal self-report assessments. The study aims are to: 1. Test the effectiveness of NPOWER365 in improving daily and longer-term (1-6 months) HIV-related behavioral health (primary outcome: ART adherence) and psychological health (e.g., secondary outcomes: lower depressive and anxiety symptoms) in a 6-month waitlist randomized controlled trial with 350 men living with HIV in the four Atlanta-area Ending the HIV Epidemic (EHE) jurisdictions. 2. Examine the moderating effect of NPOWER365 on associations between daily stress and our primary and secondary HIV outcomes. 3. Evaluate NPOWER365 maintenance and reach at the user-level (e.g., within-user changes in engagement and daily effects) and setting-level (e.g., intervention adaptations, community uptake). This research will provide critical evidence for the impact and scalability of NPOWER365 as a sustainable, community-centered intervention designed to improve HIV care in high-need, low-resource settings.

NIH Research Projects · FY 2025 · 2023-07

“Therapeutic inertia,” defined as a lack of timely adjustment to therapy when a patient’s treatment goals are unmet, is a major drive of poor outcomes in type 2 diabetes (T2D). This issue is especially pronounced among individuals enrolled in Medicaid (MA), who face challenges at three levels: patient (e.g., limited resources, low health literacy, and disproportionate access to care), clinician (e.g., lack of time or inadequate cultural sensitiv- ity), and health system (e.g., insufficient decision support or patient panel management). One way to address the complex challenges of chronic disease management is with multi-level health information technology (HIT)- supported behavioral interventions. Such interventions combine changes to clinical workflows and self-man- agement support to help patients track disease electronically, transmit data to clinicians, and receive feedback for adjusting treatment. Currently, minimal data exist to inform optimal design, implementation, and use of such multi-level behavioral interventions for patients with insulin-treated T2D on MA. A multi-level app-based inter- vention may improve outcomes. Work to date has identified the need for greater attention to patient needs; use of insulin; adherence to testing guidelines; and addressing social determinants of health and mental-health concerns. In clinic interviews, health professionals indicated the need for creative visual aids to tailor teaching (e.g., including screenshots of food from patients' local stores); using patients' data as teaching examples; "meeting patients where they are" strategies to help them utilize resources; and tailoring HIT training by patient needs. To facilitate clinician-patient communication, health professionals required clinic support for staff work- flow and customize MyChart message templates by patient needs. This project will develop and pilot-test a nurse-led, app-based behavioral intervention consisting of three evidence-based interventions: (1) education about A1C results and setting goals via MyChart, the patient portal in the Epic electronic health record; (2) a diabetes problem-solving action plan developed by clinicians in collaboration with their patients; and (3) remote monitoring via mySugr, a diabetes app, to analyze blood glucose and identify the need to adjust treatment. The proposed work includes a patient focus group study to help tailor the intervention, and a pilot study at two clin- ics to assess the feasibility of the intervention for patients with insulin-treated T2D. The project will support a future proposal for a pragmatic trial to assess the effectiveness of a multi-level app-based behavioral interven- tion for patients with insulin-treated T2D.