Rutgers Biomedical And Health Sciences

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Gastrointestinal motility disorders in childhood include rare but life-threatening conditions of Hirschsprung's disease and pediatric intestinal pseudo-obstruction and common conditions termed disorders of gut-brain interaction, including irritable bowel syndrome, functional abdominal pain, constipation, and dyspepsia. These conditions create a substantial burden through chronic health issues and lower quality of life. Hirschsprung and pediatric intestinal pseudo-obstruction are well-understood to be due to abnormalities in the enteric nervous system (ENS), which controls motility, secretion, absorption, and blood flow. Mounting evidence suggests that unrecognized abnormalities in ENS and nervous system development may also predispose to disorders of gut- brain interaction. It follows that disruption of fetal development of the ENS could result in a range of motility disorders and identification of potential disruptors could lead to novel opportunities for prevention. The objective of this proposal is to determine whether antidepressant exposure in pregnancy increases the risk of various pediatric gastrointestinal motility disorders and disorders of gut-brain interaction. We hypothesize that modulation of serotonin, norepinephrine, and dopamine through antidepressant exposure during fetal development, essential for development of the ENS and for maintaining daily functioning of the GI tract, will have long-term effects on ENS function. Animal data has demonstrated this potential, but limited human data exist. To fill this substantial gap in knowledge, we will assess the association between antidepressant use in pregnancy and pediatric motility and disorders of gut-brain interaction using three large healthcare utilization databases in the US and the UK. Specifically, we will estimate the association between in utero exposure to antidepressants and life-threatening GI motility disorders (Aim 1), and common disorders of gut-brain interaction (Aim 2). In both aims, associations of each antidepressant class and individual medications will be explore, as well as gestational timing of exposure. Multiple sources of confounding by indication, familial susceptibility, and environment will be addressed using propensity score methods and through design techniques, including use of various comparator groups, sibling comparisons, and negative control exposures. Acknowledging the complex etiology of disorders of gut-brain interaction, Aims 2.1-2.3 will assess whether various early life stressors (neonatal factors, childhood mental health, and maternal mental health in childhood) are causal mediators or modifiers of the association between antidepressant exposure and disorders of gut- brain interaction. These sub-aims will provide critical insight into causal pathways and interventions. This work will produce generalizable and actionable results that will lead to improvements in preventing these debilitating pediatric GI conditions.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Our central hypothesis is that the intestinal Clostridium bacterial community of the human gut microbiome capable of 7𝛼-dehydroxylation conversion of primary to secondary bile acids is an underlying mechanism of clinical gallstone disease. Bacteria performing 7𝛼-dehydroxylation, which humans are not capable of, are the potential cause of this painful metabolic condition requiring more abdominal surgery than any other digestive disease. We will use metagenomics, metatranscriptomics, targeted metabolomics, and pharmacoepidemiology as complementary techniques for comprehensive understanding of the microbiome performing 7𝛼- dehydroxylation function and clinical gallstone disease. First, we will study the 7𝛼-dehydroxylation bacteria and its genetic expression of this function, comparing those with inflammatory bowel diseases to healthy volunteers. Our rationale for studying inflammatory bowel diseases is that it will help us detect 7𝛼-dehydroxylation bacteria and function in patients with higher incidence of gallstone disease than in the general population. We will use robust publicly available datasets of human fecal samples to obtain necessary metagenomic and metatranscriptomic data. Second, we will compare the 7𝛼-dehydroxylation function in patients who have and do not have asymptomatic gallstones, again in patients with inflammatory bowel diseases, as well as in those who have and do not have symptomatic gallstones that require surgery. Studying clinical phenotypes of no disease, asymptomatic disease, and symptomatic disease will help us understand the 7𝛼-dehydroxylation microbiome function. We will do this using genetic sequencing and mass spectrometry techniques on patients’ fecal, serum, oral, and urine samples. We will detect important 7𝛼-dehydroxylation bacteria understanding mechanistic gene expression and function (metatranscriptomic and targeted metabolomic data, respectively). Third, we will study the impact of antibiotics effective against Clostridium, which are known to be 7𝛼-dehydroxylation bacteria, on the incidence of clinical gallstone disease in humans. We will do this using population-level data of drug exposures (pharmacoepidemiology). We have used these approaches previously to study other conditions; understanding the functional role of the microbiome in symptomatic kidney stones; and antibiotics’ impact on children’s microbiome-related disorders. Now, we have preliminary data that strengthen our rationale for studying Clostridium species and clinical gallstone disease. We have assembled a unique team with expertise in genomic bioinformatics, computational and molecular biology, analytic chemistry, patient-oriented research, clinical epidemiology, pharmacoepidemiology, and biostatistics. They have relevant and complementary knowledge and skillsets to expand understanding of clinical gallstone disease as a preventable bacterial-driven metabolic disease in humans. We will generate new evidence with important epidemiologic and clinical implications for disease prevention. This research will inform future projects about non-surgical therapeutic targets, such as antibiotics or vaccination, and the eventual prevention and eradication of clinical gallstone disease.

NIH Research Projects · FY 2026 · 2026-02

Project Summary The majority of Parkinson’s disease (PD) cases are not caused by an inherited monogenic mutation, and disease etiology involves a combination of genetic and environmental factors. Epidemiological studies show that pesticide exposure, particularly to organochlorine pesticides such as dieldrin, increases the risk of sporadic PD. In a model of increased PD susceptibility, mice exposed to dieldrin during development show male-specific increased susceptibility to adult exposure to the dopaminergic toxicant MPTP and, in data from our previously NIEHS-funded work, α-synuclein (α-syn) preformed fibrils (PFFs). Results in this two-hit model demonstrate that developmental exposure to dieldrin leads to largely sex-specific changes in epigenetic modifications from birth to 9 months of age within pathways related to critical steps in early neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, synaptic plasticity, and glial-neuron interactions, suggesting that developmental dieldrin exposure disrupts critical neurodevelopmental pathways, thereby impacting risk of late-life diseases, including PD. However, the early neurodevelopmental effects of this exposure remain incompletely understood. In addition, while these effects are thought to be mediated by direct impacts of dieldrin on the developing brain as dieldrin crosses the placenta and can be detected in the neonatal brain, disruption of placental serotonin (5HT) has emerged as a potential indirect mechanism of developmental neurotoxicity (DNT). Because the placenta is the primary source of 5HT for the developing fetal brain and proper regulation of placental serotonin is essential for proper fetal neurodevelopment, disruption of placental 5HT can cause behavioral and neurological changes throughout the lifespan. Such disruption by genetic, pharmacologic, or toxicologic mechanisms increases the risk of neurodevelopmental disorders, but long-term outcomes on late-life diseases are largely unexplored. This grant aims to test two related yet independent hypotheses. In Aim 1, we hypothesize that dieldrin, known to disrupt monoaminergic systems in the adult brain, may also affect these systems within the placenta; this disruption of placental 5HT may be an additional indirect mechanism of DNT. In Aim 2, we hypothesize that developmental dieldrin exposure alters the development of fetal and neonatal monoamine systems.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Diabetic neuropathic pain (DNP) is a major public problem. Current successful treatment for this disorder are highly limited because most medications used are ineffective and non-specific. Changes of gene expression in primary sensory neurons of the dorsal root ganglion (DRG) are believed to be the underlying molecular basis for the pathogenesis of DNP. Understanding the expression and function of DNP- specific gene in the DRG may provide highly precise and effective therapy for this disorder. We recently identified a DNP-specific circular RNA that is 100% identical between mouse and human and upregulated only in the DRG neurons from the mice with type 1 diabetes mellitus (T1DM) and from the mice and human donors with type 2 diabetes mellitus (T2DM). Because it is formed by back splicing from exon 4 to exon 2 of the Rps6kb1 pre-RNA, we named it cRps6kb1 (cRps). cRps upregulation may be due to an increase in the expression of heterogeneous nuclear ribonucleoprotein L (HNRNPL, an RNA-binding protein/alternative splicing factor) in the diabetic DRGs. Blocking this upregulation alleviated nociceptive hypersensitivity in diabetic mice, likely through a loss of competitive binding of cRps to PUM2 (Pumilio RNA-binding family member 2, a translational repressor) and corresponding increase in PUM2 interaction with the 3'-untranslated region of C-C chemokine ligand 2 mRNA (Ccl2 3'-UTR), leading to translational inhibition and degradation of Ccl2 mRNA in the diabetic DRGs. Giving that CCL2 is a driver in the genesis of neuropathic pain, DRG upregulated cRps is responsible for DNP likely through CCL2 increase in the DRG. This proposal will further examine whether and how DRG cRps contributes to DNP. In Specific Aim 1, we will determine whether blocking cRps upregulation in the DRGs alleviates established nociceptive hypersensitivity under the conditions of streptozotocin (STZ)-induced T1DM and diet-induced obesity T2DM. We will also investigate whether mimicking DRG cRps upregulation produces DNP-like symptoms in naive mice. In Specific Aim 2, we will investigate whether cRps and HNRNPL are time-dependently upregulated and whether DRG cRps upregulation results from an increase of HNRNPL expression in the DRG neurons from mice or human donors under the DNP conditions of T1DM or T2DM. In Specific Aim 3, we will first examine whether the expression of CCL2 and its receptor CCR2 is time-dependently increased in the diabetic DRGs and if CCL2 increase is required for nociceptive hypersensitivity under the conditions of STZ-induced T1DM or diet-induced obesity T2DM. We will then examine whether cRps upregulation contributes to CCL2 increase in diabetic DRG neurons. Finally, we will explore whether cRps upregulation increases its competitive binding to PUM2, leading to a consequent release of Ccl2 3'-UTR from PUM2 binding and the promotion of translational activity and stability of Ccl2 mRNA in diabetic DRG neurons. Completing this proposal will not only identify a previously unknown mechanism underlying DNP but may also provide promising treatment of this disorder.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Food and environmental allergies are a significant health burden in developed countries. However, it remains still unclear why some allergy patients develop systemic, potentially fatal anaphylactic responses even after a local allergen exposure (e.g., acute hypothermia upon bee sting), while others experience localized reactions in the areas not directly exposed to the allergen (e.g., skin manifestations of food allergy). Numerous studies indicate the critical involvement of allergen-specific IgE antibodies in acute allergy and anaphylaxis, but high levels of IgE against a particular allergen do not always induce anaphylaxis or an ectopic reaction in a remote site upon exposure to that allergen. Thus, in addition to the dose of IgE and the allergen, there appears to be unknown factors affecting the severity and organ specificity of allergic responses. However, the host’s mechanism responsible for the systemic and ectopic dissemination of allergic reaction remains unclear. One of the current limitations to address this question is the lack of animal models, as most animal models of severe allergy requires systemic or repeated challenge with a high dose of allergen, making it often challenging to definitively address how the allergic response is originated. Proteases are a common type of allergens. Papain, a cysteine protease in papaya and a known occupational allergen, is widely used as an experimental adjuvant to induce type 2 inflammation in mice, but papain-specific allergic response has not been well-characterized. We recently found that a second exposure to papain in previously exposed animals induces prolonged edema and hypothermia, a hallmark of local and systemic anaphylaxis, respectively. In contrast to most animal models of systemic anaphylaxis in which the allergen is systemically administered, the systemic response is induced by local sensitization and a single challenge in our model, making it an ideal model to study how the local challenge leads to disseminated responses. We here propose to use this new model in combination with cutting-age mouse genetic and transcriptomic approaches to dissect how a local challenge induces systemic anaphylactic response and ectopic inflammation in a remote site. We hypothesize that local MCs and neurons coordinately trigger systemic and ectopic responses in allergic reactions. In this application, we aim to understand (1) how local challenge develops into a systemic allergic response, and (2) how the allergen-specific immunity modulates local immune responses to protease allergens. If successful, future studies will follow to investigate the molecular mechanism and therapeutic intervention, to examine its relevance in responses to other allergens, and to extend the knowledge to other clinically relevant organ systems such as food and airborne allergies.

NIH Research Projects · FY 2026 · 2026-02

Abstract: The cytokine IFN-g controls both protective and pathogenic host responses during infection and inflammation. By activating cell autonomous antimicrobial mechanisms, this cytokine mediates host resistance mechanisms that control pathogen replication. Much less is known about how the same cytokine regulates sickness associated behaviors such as anorexia and whole-body weight loss. We have recently published data indicating that IFN-g regulates the systemic levels of the stress hormone GDF-15 which is important for appetite suppression and weight loss during infection. In turn, GDF15 is required for hepatic production of FGF21 and the consequent generation of ketone bodies, including beta-hydroxybutyric acid. Recently, a previously unrecognized biochemical pathway of “reverse proteolysis”, mediated by the enzyme CNDP2 (carnosine dipeptidase 2) has been shown to generate a novel class of anorexigens through chemical conjugation of either beta-hydroxybutyric (BHB) acid or lactic acid to amino acids bearing hydrophobic side chains. While a role for this new pathway has recently been demonstrated in the context of appetite suppression following metformin therapy or physical exercise, its relevance to sickness associated anorexia during infection and inflammation has not been examined. Here, we present preliminary data showing that BHB-amino acid but not lactoyl-amino acid conjugates are elevated in the serum of T. gondii-infected mice. Furthermore, the in vivo expression of CNDP2 transcripts is upregulated during infection and this induction is dependent on IFN-g receptor signaling. Thus, we hypothesize that IFN-g mediates suppression of food intake and sickness associated weight loss, in part, by inducing CNDP2 in immune cells, thus, elevating circulating levels of this novel class of metabolite-derived anorexigens during infection. Specific Aim 1 will test the hypothesis that IFN-g signaling induces CNDP2-mediated generation of BHB-amino acids by immune cells during T. gondii infection. Specific Aim 2 will critically interrogate the role and function of CNDP2 in regulating the sickness associated anorexia and weight loss during T. gondii infection. Completion of this project will provide novel and fundamental insights into how inflammation and immune cytokines control sickness associated anorexia and weight loss during infection and inflammation. These insights may provide avenues to promote health by decreasing disease sequelae that result from hyperactivation of immune response and the ensuing disruption of metabolic homeostasis in the host.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Staphylococcus aureus is a major human pathogen that is a common cause of hospital and community acquired pneumonia, both of which lead to significant morbidity and mortality. Increasing antibiotic resistance and prevalence of methicillin resistant strains is of critical concern. The long-term goal of our research is to better understand the host-pathogen interaction between S. aureus and the host innate immune system. It is hoped that an improved understanding of this interaction could lead to novel therapies targeting the bacterium or modulating the host to thwart this multidrug resistant pathogen. The objective of this proposal is to understand how type III IFN contributes to the pathogenesis of S. aureus infection. The rationale for this approach is that new targets are needed to either develop antibiotics/inhibitors or vaccines against S. aureus. Studies investigating type III IFN to-date are largely focused on viral infections where activation of signaling is important to control the infection. We have shown that type III IFN signaling contributes to the pathogenesis of acute S. aureus pneumonia. We have demonstrated alterations to the alveolar macrophage population can improve bacterial clearance by manipulating the pathways identified from our RNA-seq analysis. Investigation of both differential transcripts and proteins indicates changes to the epithelial barrier occur when type III IFN signaling is present. We also have data that shows that S. aureus strains can activate type I and III IFN signaling with variable intensity and independent of each pathway. Precise mechanisms for this involvement of type III IFN signaling are still lacking. This contribution is significant as it will provide a deeper understanding on how the type III IFN pathway influences the clearance of S. aureus from the airway. Completion of our objectives will be accomplished by pursuing two specific aims: 1) Determining the role of type III IFN in pathogenesis through studies on MID1 in alveolar macrophages, the role of IL-1β in immunopathology its effect in the airway barrier and 2) defining how S. aureus activates type III IFN, its comparison to type I IFN signaling and the utility in targeting this pathway. The innovation of this research is both conceptual and technical. The concept that the pathway is inhibitory to bacterial clearance through the epithelial response to type III IFN signaling is unique. We will examine both direct effects on airway epithelial cells as well as the effects IFN signaling has on professional phagocytes. It is also thought activation of type I&III IFN is linked, and we provide evidence this is not entirely the case. We will utilize techniques across multiple fields, microbiology, immunology, cell and molecular biology, utilizing a well-tested animal model of pneumonia, in vitro functional and primary cell culture assays and global approaches to understand the host response such as RNA-seq. At the conclusion of these studies, we will have expanded our knowledge on how an innate signaling pathway can impact negatively on acute bacterial infection in the airway, how this pathway can be activated and how it can coordinate multiple cells in response to its activation.

NIH Research Projects · FY 2026 · 2026-02

Abstract Epilepsy is a severe neurological disease affecting more than 65 million people worldwide and is characterized by unpredictable abnormal electrical discharges resulting in recurrent seizures. About one third of patients with epilepsy suffer from intractable seizures that do not respond to anti-seizure medications (ASMs). Neurosurgical interventions and neurostimulator devices are useful options for only a fraction of patients with drug-refractory seizures, underscoring the urgent need to develop new therapies. One strategy with considerable promise is to engraft new neurons to provide enhanced GABAergic inhibition in an activity-dependent manner. However, use of fetal neurons for cell therapy is associated with practical and ethical issues. Therefore, to overcome such hurdles, in our previous studies, we pioneered the transplantation of human pluripotent stem cell (hPSC)- derived medial ganglionic eminence (MGE)-type human cortical interneurons (cINs) into epileptic mouse brains and demonstrated their integration into dysfunctional circuitry, accompanied by the suppression of seizures and comorbid behavioral abnormalities. Furthermore, more recently, we have determined the optimal stage of human cIN differentiation to ensure maximal integration into host circuitry as well as safety without risk of tumor formation, and developed a method to efficiently generate these safe and highly migratory populations of synchronized early postmitotic cINs from hPSCs in large quantities, bringing cell therapy for epilepsy one step closer to reality. Furthermore, we have successfully tested the efficacy of human early postmitotic cINs in 2 different models of temporal lobe epilepsy (TLE), observing >80% of seizure reduction. With these strong previous studies, now we are ready to embark clinical translation of this novel and restorative therapy for epilepsy patients with limited options. Thus, in this proposed study, we will scale up production of synchronized early postmitotic cINs that are optimal for grafting under cGMP condition. For added safety, we will utilize well- characterized HLA-edited hypoimmunogenic iPSCs to minimize the need for immunosuppression for off-the- shelf use of human cINs. We will also extensively analyze the produced early postmitotic cINs’ phenotype, efficacy, safety, tumorigenesis and biodistribution to seek IND approval. Once we obtain IND approval, we will do a first-in-human clinical trial of early postmitotic cIN grafting with a primary goal of safety analysis, while also checking efficacy as a secondary measure. This will be done in patients with intractable TLE who are candidates for resection while they undergo intracranial EEG to identify the seizure focus without additional invasive steps. Completion of these studies is pivotal for translating this experimental therapy into a viable therapeutic strategy for intractable epilepsy.

NIH Research Projects · FY 2026 · 2026-02

Substance use disorder (SUD) is a leading public health challenge, with long-term consequences for physical and mental health. In-person peer support groups are well-established as beneficial for recovery. However, as digital platforms increasingly serve as spaces for peer support, little is known about how engagement in online peer support recovery groups is associated with recovery outcomes. Emerging research has yielded conflicting results, with some studies suggesting benefits while others indicating relapse risks. This underscores the need to examine the content of discussions beyond engagement frequency. The present application seeks support for Xiangyu Tao, Ph.D., a postdoctoral associate at the Rutgers Addiction Research Center, gain the necessary training and set up a line of research to examine the role of online peer support recovery communities in SUD recovery. Specifically, she will integrate state-of-the-art artificial intelligence (AI) techniques, including Large Language Models (LLMs), with co-production to identify communication patterns and to examine their associations with recovery outcomes. LLMs offer a promising avenue for analyzing large-scale online discussions, yet they require human oversight to address challenges such as contextual misinterpretation and ethical concerns. Co-production, i.e., involving individuals with SUD recovery experience in all research stages, mitigates LLM limitations and ensures that results reflect lived experience. The mentored K99 phase will identify and characterize communication patterns in online recovery groups. Peer support and co-rumination patterns will be classified using LLMs and co-production (Aim 1); latent class analysis (LCA) will identify distinct communication profiles among users engaging in these online groups (Aim 2). During this phase, Dr. Tao will receive mentorship in co-production and AI methodologies, longitudinal data analysis and management, and responsible AI research. The independent R00 phase will build upon this foundation by examining how communication profiles are associated with recovery trajectories using longitudinal survey data from online recovery group participants (Aim 3). This project is highly innovative in its integration of LLMs and co- production to analyze large-scale digital recovery discussions, ensuring that AI-driven insights are both computationally rigorous and socially informed. Findings will enhance understanding of digital peer support for SUD recovery and will inform future mechanistic studies and SUD interventions. By identifying communication patterns associated with recovery trajectories, this project will guide digital health platforms, peer support programs, and clinicians in optimizing online recovery environments to better support individuals with SUD. This project aligns with the NIDA Strategic Plan Cross-Cutting Priority to "Leverage Data Science and Analytics to Understand Real-World Complexity" by utilizing advanced computational methods to analyze digital recovery support interactions. The project is highly significant in bridging advanced AI computational tools with the lived experiences of individuals to produce impactful research to promote substance use recovery.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT: Helminth parasites infect an estimated 2 billion people causing significant malnutrition, growth retardation and immunopathology. Further, these debilitating infections also exert enormous economic burdens on heavily infected areas. It is well established that type 2 responses initiate beneficial inflammation that promotes disease tolerance and parasite expulsion. However, when dysregulated, infection-induced type 2 immunity can lead to severe immunopathology including emphysema and fibrosis. Thus, it is essential that we gain a better understanding of how type 2 inflammation is properly balanced to develop better therapeutic strategies to treat these devastating infections and other forms of lung pathology. Our studies and those of others have also shown that lung macrophages play important roles in antihelminth immunity and insights into how this protective macrophage population is sustained may provide the basis for new therapeutics that target resistance and decreased worm burden. We have identified unappreciated and significant roles for infection-induced neutrophils and basophils in mediating these pathways. Specifically, we have discovered that lung neutrophils enhance infection-induced type 2 inflammation and macrophage activation while lung basophils restrict these responses. Collectively, these studies demonstrated that interactions between distinct innate immune cells in the lung are required to properly regulate macrophage responses post-helminth infection. The field of innate immune memory or trained immunity suggests that once activated, macrophages can maintain a level of non-specific memory resulting in enhanced effector functions following subsequent stimulation. While this is well established in the field of type 1 immunity, how macrophages are trained in the context of type 2 inflammation remains less defined. Our preliminary studies have shown that Nippostrongylus brasiliensis (Nb)-educated macrophages isolated 45 days post-infection confer enhanced resistance to Nb when transferred into the lungs of an otherwise naive host. We hypothesize that coordinated extracellular interactions with macrophages, including neutrophils and basophils, influence intracellular metabolic and epigenetic changes that mediate the development and persistence of the Nb- induced lung macrophages. We will now investigate how this long-lived macrophage phenotype is sustained. Aim 1 will focus on the role of extracellular factors including neutrophils and basophils and changes in lung architecture that may contribute to the formation and persistence of the long-lived antihelminth macrophage phenotype. Aim 2 will investigate intracellular changes in macrophages, directly examining metabolic and epigenetic changes occurring in macrophages that instruct the development and persistence of their training. In this context, we will directly examine whether intrinsic mechanisms are sufficient to support the trained macrophage phenotype. Collectively, these studies address an important knowledge gap and will provide mechanistic insight into the development of memory-like macrophages in the context of type 2 inflammation.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY / ABSTRACT The objective of the proposed research is to develop a comprehensive framework to enhance the utility and accuracy of epigenetic clocks, which are tools used to predict chronological age or aging-related diseases from DNA methylation (DNAm) levels at specific cytosine-guanine dinucleotide (CpG) sites. Despite their widespread use, current epigenetic clocks suffer from the following issues: (i) reduced predictive power when applied to diverse study cohorts, (ii) lack of prediction interval that accounts for population heterogeneity, and (iii) insufficient use of data from higher-resolution platforms. To address these challenges, this proposal sets forth several aims. First, this project will develop a heterogeneity-aware transfer learning framework to improve the generalizability of existing epigenetic clocks to different populations, tissues, or cell types. This includes creating methods to correct biases and enhance prediction accuracy by leveraging information from established clocks while overcoming data-sharing constraints. Second, prediction intervals based on mean regression produce the same width across different subpopulations. This proposed work will establish a quantile regression framework to understand better and predict variations in age acceleration across different population segments. The key idea is to employ high- dimensional quantile regression and conformal inference to build adaptive prediction intervals. Furthermore, this proposed work will create an integrative method utilizing higher-resolution DNAm data to optimize the performance of epigenetic clocks originally developed with lower-resolution data. This method will use neural network transfer learning to integrate information across spatially correlated CpG sites. Lastly, the newly proposed methods will be implemented and disseminated to the scientific community with open-source software packages. The completion of this proposal will significantly improve the generalizability, adaptability, and transparency of epigenetic age calculators, enabling them to serve diverse populations better and incorporate data from newer, higher-resolution DNAm platforms. The availability of open-source software will also support further research and application of these improved models in aging research.

NIH Research Projects · FY 2026 · 2026-01

Project Summary/Abstract This is an administrative supplement application to the parent grant to support the purchase of a new microscope system due to the unexpected failure of a critical component in our existing system. Due to the age of the existing microscope, manufacturing of the failed parts was discontinued, and newer alternatives are incompatible with the existing system. Attempts to source used parts have proved challenging, and reliance on microscopes in other laboratories or shared facilities have been inadequate, which has delayed our progress on the proposed aims because of limited scope access and other practical limitations detailed in the application. These factors underscore the need for a sustainable solution as our proposed aims rely heavily on high resolution confocal microscopy. This equipment breakdown was entirely unanticipated during grant submission and reporting periods, precluding any rebudgeting from existing funds to adequately address the loss of independent high- resolution imaging capacity. As such, an administrative supplement is requested, with the institution committing matching funds in order to fully cover the cost of the new imaging system. Several imaging systems are considered, and the proposed solution represents the most cost-effective way to restoring full research productivity.

NIH Research Projects · FY 2026 · 2025-12

Alzheimer’s Disease (AD) is the most common form of dementia in the elderly. AD brains are characterized by senile plaques composed of amyloid beta (Aβ) and intracellular tangles composed of tau. Mutations in the Amyloid Precursor Protein (APP), the protein from which Aβ is derived, cause AD, but the precise function of APP in the brain is unclear. APP undergoes complex metabolism, and its metabolites are secreted by cells in extracellular vesicles (EVs). To study the function of APP-containing EVs, we isolated App- EVs from rat primary neuronal conditioned media and proteomic analysis identified the Valosin-containing protein (Vcp) as molecular cargo. Vcp is a segregase/molecular unfoldase, a known tau-interacting protein, and a protein mutated in AD related dementias (ADRDs). In this application, we hypothesize that AD and ADRD causing mutations alter the abundance and composition of App-EVs and that this affects the target and function of App-EVs. To test this, we have proposed three aims. The first aim will investigate the molecular mechanism of App-related cargo loading into EVs. The second aim will test the effect that App-EV biogenesis has on a rat model of tau pathology, as tau is a substrate for Vcp. The third aim will test the effect of App-EVs on Vcp mutation-induced pathology. The proposed aims will leverage the Tambini lab’s significant expertise in the generation, validation and use of AD rat knock-in models and the optimization of techniques for pure App- EV isolation to address fundamental questions about the function of APP.

NIH Research Projects · FY 2026 · 2025-11

Project Summary/Abstract This CDA proposal seeks to investigate the long-term impact of modifiable health-related behaviors (e.g., smoking, exercise) on cognitive decline over time among persons with multiple sclerosis (MS; Specific Aim 1). This is important given the detrimental impact of cognitive impairment in MS, affecting symptom management, instrumental activities of daily living, and independence. Since there are no proven treatments for cognitive impairment, it is imperative to identify modifiable risk factors – specifically health-related behaviors – that can serve as potential treatment targets. Moreover, in order to modify these behaviors, this proposal will explore disease (MS)-related, person-specific, and environmental facilitators and barriers to engaging in health-related behaviors (Specific Aim 2). Such aims are consistent with the mission of the National Center for Medical Rehabilitation Research (NCMRR) to “determine the impact of modifiable lifestyle and health-related behaviors on prevention of secondary conditions, psychosocial functioning, and community participation,” as outlined in the 2016 NIH Research Plan on Rehabilitation. The Specific Aims will be accomplished via two longitudinal, observational studies among persons with MS. Cognitive trajectories will be established by standardized neuropsychological assessments. Health- related behaviors will be evaluated using self-report inventories. Facilitators/barriers to engaging in health-related behaviors will be determined by quantitative inventories and qualitative semi-structured interviews. Data from this investigation will serve as pilot data for a R01 grant in which a multicomponent lifestyle intervention to improve cognition among persons with MS will be proposed. Such intervention has been recently conducted in older adults at-risk of developing dementia, with ongoing replications around the world. Information from this project will help adapt this type of intervention to individuals with MS by accounting for MS-specific facilitators and barriers to engaging in health behaviors. I have assembled a multidisciplinary mentoring team, with expertise in clinical neuropsychology, cognitive rehabilitation, epidemiology, advanced biostatistics, clinical trial design, and digital health technology. By completing the proposed training and research plans, I will be able to achieve my training goals, including: (1) applying population-based survey research design to lifestyle behaviors; (2) learning qualitative research design and advanced statistical techniques; (3) learning how to conduct clinical trials and applications of digital health technology; and (4) honing professional skills, such as manuscript writing, grantsmanship, laboratory management, and mentorship. Achieving these goals will help me transition into an independent clinical investigator, with a long career of grant-funded research.

NIH Research Projects · FY 2025 · 2025-09

Not Applicable

NIH Research Projects · FY 2025 · 2025-09

Climate change constitutes “the single biggest health threat facing humanity”. Climate change exacerbates heat-related morbidity and mortality due to more frequent, longer and extreme heat events. It also increases wildfire occurrence and worsens air pollution, which is linked to thromboembolic and bleeding events. The health impacts of extreme heat and air pollution will only intensify as a result of the changing climate. Certain subgroups are disproportionately affected, including low-income populations. Pregnant women and their children, especially those from low-income communities, are particularly vulnerable to harms from extreme heat and air pollution, not only due to physiologic changes during pregnancy and social vulnerability, but also because of the medications that are taken in pregnancy to treat chronic diseases, mental health conditions, and pregnancy complications. Nearly two-thirds of pregnant women in the US take at least one prescription drug other than vitamins, and medication use is likely to play an important role in modifying the health effects of heat and air pollution and/or further increasing morbidity in vulnerable pregnant patients and their offspring. However, the current evidence assessing adverse perinatal outcomes in relation to heat and air pollution lacks adequate consideration of individual-level factors including medication use and interactions between medications and other risk factors. While the CDC recently published guidance for heat and medications recognizing the significance of environment-medication interactions, evidence is still limited, especially for pregnant women. In the present proposal, an interdisciplinary team of experts in climatology, environmental and pharmacoepidemiology, obstetrics, congenital abnormalities, data science, and biostatistics will work closely to design a series of observational epidemiologic studies. We will link temperature/humidity and air pollution data with national Medicaid data as well as birth registry data from New Jersey, Massachusetts and California and analyze the linked data using the state-of-the art study designs and analytic methods. Our study aims to: (1) assess the independent and synergistic effects of extreme heat and prescription opioids and other heat-sensitizing medications on heat-related adverse events in low-income pregnant women; (2) assess the independent and synergistic effects of air pollution, i.e., particulate matter (PM2.5), and medications associated with thromboembolic and bleeding events on these outcomes; and (3) assess the independent and synergistic effects of extreme heat/air pollution and potentially teratogenic medications on the incidence of congenital abnormalities. The results of our study will quantify the effects of extreme heat and air pollution exposure and their potential interactions with medication use in low-income pregnant women while also shedding light on potential mechanisms that confer increased risk to certain individuals. The evidence generated from our study will have a direct impact in shaping adaptation strategies and policies for climate change to protect vulnerable populations from the effects of extreme heat and air pollution.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Chronic alcohol use disorder (AUD) is associated with neurostructural damage and a pervasive pattern of cognitive deficits, which persist even in detoxified individuals. It has been hypothesized that deterioration of the blood brain barrier (BBB) provides a primary causative mechanism through which repeated high dose exposure to alcohol leads to neuroinflammation, neuronal death and cognitive impairments in chronic AUD. To date, evidence for a role of BBB alterations in the long-term consequences of chronic AUD comes largely from preclinical studies. Although some human post-mortem data support the idea of BBB dysfunction in AUD these data are limited and basic questions about the magnitude and spatial extent of BBB dysfunction, its antecedents, developmental course and its consequences remain unaddressed. A recently developed MRI technique using motion corrected diffusion weighted pseudo-continuous arterial spin labelling (MCDW-pCASL) sequence provides the ability to noninvasively measure water permeability across the BBB and quantify water exchange rate (Kw) in vivo. Critically, this approach is sensitive to more subtle changes in the BBB, whereas earlier methods could only assess the permeability of large molecules. Moreover, because the approach is noninvasive and does not involve injection of contrast agents, it can be implemented in longitudinal and larger scale studies. We propose to develop a research program utilizing this technique to map Kw alterations and determine their correlates in chronic AUD. In an initial pilot-feasibility step of this research program, we propose to scan 30 recently detoxified individuals with a history of severe chronic AUD and 30 age and sex matched controls with the MCDW-pCASL sequence. We will test the hypothesis that chronic AUD is associated with reduced BBB integrity as reflected in altered Kw and will determine how regionally diffuse or specific these alterations are. We will also collect data on drinking history (age of first heavy drinking, total alcohol consumed over lifetime, frequency of binge drinking) to determine the extent to which this history predicts the magnitude of alterations in the BBB. We will also collect high-resolution structural MRI measures of grey matter volume/cortical thickness and diffusion tensor imaging of white matter microstructure, as well as measures of cognitive functioning and premorbid IQ to test hypotheses that the magnitude of BBB alterations predict the neural and cognitive deficits associated with chronic AUD. If successful, these studies will support the development of large-scale studies to understand the evolution and impact of BBB alterations in AUD. This line of work could have significant clinical implications given the recent development of techniques for targeting BBB structure and function. Indeed, if the MCDW-pCASL sequence proves sensitive to BBB dysfunction in AUD, it could potentially be used as a precision medicine technique to identify those individuals who might benefit from BBB interventions and to directly monitor the impact of those treatments in vivo.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Hypertensive disorders during pregnancy (HDP) and gestational diabetes (GDM) represent the foremost complications in pregnancy, significantly contributing to global maternal and fetal morbidity and mortality. Effectively managing HDP and GDM hinges on regular monitoring of blood pressure (BP) and blood glucose (BG) to ensure adequate control and timely interventions for maternal and fetal well-being. However, in low-income settings like Nepal, women encounter difficulties in making frequent healthcare visits due to logistical challenges, thereby exposing them to risks of uncontrolled BP and BG levels. Telemonitoring offers a promising and cost-effective alternative by enabling pregnant individuals to monitor BP and BG at home and share real-time results with healthcare providers, which in turn facilitates informed clinical decision-making and timely interventions. While remote monitoring has been proven effective in improving BP, BG, and perinatal outcomes among women with HDP and GDM in high-income countries, its implementation faces challenges in low-resource settings like Nepal. In our pilot study [R21TW011377-S1], we developed the MOM-HD (Mobile-based Obstetric Monitoring for Hypertension and/or Diabetes) to address pre-identified barriers by providing financial and technical assistance for patient self-monitoring of vital signs and delivering comprehensive training and technical support to healthcare providers, including developing standardized clinical algorithms and quality assurance protocols to facilitate seamless workflow. Based on promising findings from our pilot work, here we propose to conduct a Hybrid Type II Effectiveness-Implementation Randomized Controlled Trial (RCT) to assess the effectiveness and evaluate the implementation of our MOM-HD program in real-world clinical settings in Nepal. To address the study aims, we will recruit 864 women who are newly diagnosed with HDP and GDM from three metropolitan hospitals and randomly assign them to either (i) MOM-HD + standard care or (ii) standard care alone, from enrolment in pregnancy to 6 weeks postpartum. Primary and secondary clinical outcomes will be assessed at delivery, and at 6 weeks postpartum. We hypothesize that compared to standard care, the use of MOM-HD in addition to standard care will result in lower systolic BP levels, lower incidence rate for the composite adverse perinatal outcome of either perinatal loss, neonatal intensive care unit admission, primary cesarean delivery or labor induction, and lower proportion of days with elevated systolic BP or BG readings between recruitment and 6 weeks postpartum. A convergent mixed-methods approach will be used to assess implementation and maintenance outcomes using the RE-AIM framework, and economic sustainability will be assessed by collecting primary cost data. If successful, the study would yield effective implementation strategies to implement a mobile-based telemonitoring program and enhance clinical management and outcomes among pregnant women with HDP and GDM in other low-resource countries. Findings from this study will also develop the knowledge, tools and processes needed to broadly disseminate and scale evidence-based telemonitoring interventions for HDP and GDM in diverse settings.

NIH Research Projects · FY 2026 · 2025-09

ABSTRACT Nicotine pouches are oral, spit-free products that contain nicotine; while they resemble smokeless tobacco (SLT) products, they contain nicotine powder rather than tobacco leaf. Sales of nicotine pouches have skyrocketed in recent years and these products now account for more than 40% of the smokeless market share. Interest in and use of nicotine pouches appears to be greatest among people who use other tobacco products, including cigarettes, e-cigarettes, and SLT. As non-combustible products with no tobacco leaf, no vapor, and no inhalation, nicotine pouches hold potential for harm reduction, and data indicate that nicotine pouches are more similar to medicinal nicotine replacement therapy than to tobacco. Nicotine pouches could have a positive impact on population health if adults use pouches to quit tobacco or switch to exclusive pouch use, provided that tobacco- naïve young people do not initiate regular use; the harm reduction potential for these products is limited if dual or poly product use is the dominant pattern. However, the trajectories of tobacco and nicotine product use among adult tobacco users who have purchased and tried nicotine pouches remains unknown, making it difficult to assess the potential public health impact of these products. Further, there are no studies that investigate detailed nicotine pouch use behavior, contexts of use, and changes over time among adults who use tobacco at the national level. This mixed methods R01 application will employ a nationally representative longitudinal survey study, integrated with qualitative interviews, to advance the scientific understanding of nicotine pouch use at the population level, generally among adults and specifically among those who use other products. Our study will answer important questions about who is using nicotine pouches, reasons for use, methods, frequency, and intensity of use, indicators of dependence, and product characteristics that influence use. Improved knowledge about each of these factors is critical for understanding of the impact of these products on public health. We will conduct a nationally representative 5-wave longitudinal web survey of 500 adults with a history of cigarette, e- cigarette, or SLT use who currently (past month) or recently (past 6 months) used nicotine pouches to characterize people who recently tried or use nicotine pouches and identify predictors of pouch adoption (regular use) and progression to exclusive pouch use (Aim 1). With quarterly data collection, we will examine trajectories of nicotine pouch use, including changes in frequency and intensity of pouch use, use of other products, and nicotine dependence indicators over a 15-month period (Aim 2). We will also evaluate predictors of trajectories and hypothesize that adults who transition to or maintain exclusive nicotine pouch use will exhibit lower nicotine dependence than those who use multiple products. Finally, we will conduct semi-structured interviews with a subset of survey participants at 3 time points to gain deeper understanding of how users differentiate various oral tobacco and nicotine products, reasons for trying oral nicotine, reasons for continuing (or discontinuing) pouch use, methods of pouch use, and perceptions about product brands and characteristics (Aim 3).

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The cause of Crohn’s disease (CD) is believed to be rooted in the interactions between genetic susceptibilities and exposures to environmental factors, such as specific gut microbes. Unfortunately, the complexity of these interactions makes it difficult to understand what portion of CD risk is modifiable, and specifically whether gut microbiome compositions can be altered to overcome one’s underlying and fixed genetic predisposition. This proposal will generate additional data for an ongoing study addressing whether individuals at high genetic risk for CD, but who never develop the disease, harbor transferrable gut microbial signatures that mediate disease protection. Aim 1 of this proposal entails the generation of shotgun metagenomic sequencing data on samples already collected from multiplex CD families – with the rationale that families, sharing common living environments, meals, and behaviors, will minimize frequent confounders of human microbiome studies. Individuals have been stratified by a polygenic risk score to identify those at highest genetic risk but remain disease-free, and who are hypothesized as being most likely to harbor CD-protective intestinal microbes. The generated shotgun sequencing will allow us to determine bacterial community functions and thus integrate our 16S sequencing and fecal metabolomic data in an effort to develop a mechanistic understanding of the relationship between the gut microbiome and CD development. In Aim 2, we will leverage our access to pre- generated multi-omic data from a large biobank to extend our investigation beyond a multiplex family context. The data generated in this proposal, therefore, will provide key insights to our study of microbially-mediated modulators of CD risk and disease activity.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Gestational weight gain (GWG) has important implications for maternal and child health and is an ideal modifiable factor to improve short- and long-term health outcomes among women and children. Here we propose to develop and test a game-based mobile app (GWG-DH) to prevent excessive gestational weight gain (GWG) and limit postpartum weight retention (PPWR) among women in Nepal who enter pregnancy with overweight and obesity (BMI≥25 kg/m2 ). In the R21 phase, we will apply a user-centered agile design approach to adapt our existing app GDM-DH (developed to support diet/lifestyle modification in Nepalese pregnant women with gestational diabetes) and expand and refine it to make a game-based weight management app (GWG-DH) that matches the needs and technological sophistication of our target users (Nepalese pregnant women with overweight and obesity). The R33 phase will employ a Type I Hybrid Implementation Science Framework to test the efficacy of the GWG-DH intervention against standard care via a randomized control trial (RCT), while also evaluating its potential for implementation in real-world settings. In Year 1, we will select content modules and features for the GWG-DH app based on evidence review, theory-based behavioral change techniques, and expert discussions. Next, we will conduct design workshops with 18 target users to customize the features and game elements to match user preferences and ensure cultural relevance. Following this, we will create the app’s prototype and conduct interviews with 5 health providers and conduct 3 rounds of focus groups with target users (n=18), asking them to view the app prototype and provide feedback on its features, functions, and content. In Year 2, the revised GWG-DH app will undergo usability testing (n=27), followed by the full development of the app (beta version), and 3-month Beta testing (n=27) to assess its functionality, usability, and acceptability. With iterative refinements of the beta versions, we will build the final ready-to-test version of the GWG-DH for evaluation in the R33 phase (Years 3-5). For the RCT, we will recruit 360 pregnant women with pre-pregnancy BMI≥25 kg/m2 and randomly assign them into either (A) standard care, or (B) GWG-DH app + standard care, with up to 1 year of intervention, from 16±2 gestational weeks to 6 months postpartum. Potential mediators will be assessed at 34±3 gestational weeks and 3 months postpartum. Primary (weight) and secondary (diet/lifestyle) outcomes will be assessed at 34±3 gestational weeks, delivery and at 6 months postpartum. We hypothesize that compared to standard care, the use of GWG-DH app in addition to standard care will result in a lower rate of excessive GWG, lower PPWR, better diet quality, and greater level of physical activity during pregnancy and postpartum. Concurrent with the RCT, we will conduct a mixedmethods implementation and evaluation of the GWH-DH app, following the RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework. Findings from this study will support the dissemination and scaling of evidence-based GWG interventions across various settings, including low-resource areas in the U.S. and maternity care deserts, where access to maternal health services is limited.

NIH Research Projects · FY 2025 · 2025-09

EXECUTIVE SUMMARY/ABSTRACT The increasing frequency and intensity of wildfires are having serious public health consequences. Wildfire exposures have adverse health impacts, but the specific mechanistic effects remain unknown, especially for wildland-urban-interface (WUI) fires. Due to the burning of human-made structures as well as biomass in WUI fire episodes, the particulate matter with aerodynamic sizes less than 2.5 microns (PM2.5) generated from WUI fires, (WFPM2.5), maybe more toxic than urban background PM2.5, which is mostly generated from fossil fuel combustion, or pure biomass WFPM2.5. Such wildfire exposures will have devastating health consequences, especially in those with existing disease such as asthma and COPD. In January 2025, catastrophic WUI fires impacted Los Angeles(LA), resulting in a severe air pollution event with high PM concentrations. During this event, in collaboration with UCLA, we deployed state- of-the-art instruments in two locations to collect air quality data and size-fractionated WFPM for physicochemical characterization and toxicological assessment. The WFPM samples are stored at 4°C, and their physicochemical and toxicological properties must be analyzed in a timely manner to avoid degradation. The proposed interdisciplinary project consists of two Aims and focuses on the impact of WFPM on respiratory health. In Aim 1 we will perform detailed physicochemical analysis of the collected PM0.1 and PM0.1- 2.5 size fractions, including: i) X-Ray Fluorescence (XRF) for 28 trace elements; ii) Thermal Optical Carbon (TOC) analysis of organic carbon (OC) and elemental carbon (EC) fractions; iii) GC-MS analysis of 105 polyaromatic hydrocarbons (PAHs); and iv) ICP-MS analysis of metal content;. In Aim 2 we will employ 1). a translational ex vivo human precision-cut human lung slice (hPCLS) model and an in vitro primary cultured HASM cell model to assess the effects of WFPM on airway function, including effects on bronchoconstriction/dilation, excitation-contraction (E-C) coupling pathways, and secreted inflammatory mediators; and 2). An in vitro THP-1 macrophage model to evaluate the effects of WFPM on the health and innate immune function of alveolar macrophages, including multiple toxicity endpoints as well as phagocytosis and killing of Acinetobacter baumannii, a prevalent cause of secondary bacterial pneumonia The proposed time-sensitive work will provide a detailed physicochemical characterization of WUI WFPM in LA in comparison to non-WUI WFPM and traffic-related PM, as well as its relative toxicity and effects on respiratory health and will support the main hypothesis that WFPM from WUI fires is more toxic compared to background PM. Findings and WFPM samples from this study are timely needed by public health risk assessors and will also support future epidemiological and mechanistic studies on WUI fires and help develop remediation strategies to protect the health of impacted communities.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Improving maternal, infant and child health and wellbeing (MCH) is an urgent public health priority. Birthing people are experiencing increases in severe maternal morbidity (SMM) and other pregnancy-related health conditions, while infant mortality in the first year of life remains greater in the U.S. than any other higher- income country. There are substantial racial and ethnic inequities and disparities in MCH, which are strongly influenced by social determinants. Thus, successfully advancing MCH in the U.S. requires interventions that address underlying factors that affect health among disinvested communities, such as housing. Homelessness is a growing phenomenon in the U.S. More than 1.2 million people experience homelessness each year, and the number of people experiencing homelessness on a single night has been rising each year since 2016. Women and girls are one of the fastest growing demographic groups among people experiencing homelessness (PEH), and 4% of all birthing people experience homelessness in the year prior to delivery. Health outcomes and behaviors associated with homelessness, such as lacking access to a regular source of medical care, are known risk factors for pregnancy-related morbidity and adverse birth outcomes. Members of racial and ethnic minoritized groups, who are more likely to face health-limiting systemic disadvantages, are overrepresented among PEH, further exacerbating inequities in MCH. However, critical gaps in our understanding of how homelessness affects MCH, and how evidence-based housing services affect MCH, limit our ability to implement effective interventions. Our overall objective is to assess how and when the experience of homelessness affects maternal and infant health and racial and ethnic health inequities, and whether Permanent Supportive Housing (PSH) and Rapid Rehousing (RRH) interventions have a positive impact on these outcomes. Our multidisciplinary team will apply quasi-experimental methods to linked administrative data that include homeless and housing service information, Medicaid claims, all-payer hospital records, and birth records. In Aim 1, we estimate effects of homelessness on maternal health conditions, health behaviors and healthcare utilization during pregnancy. In Aim 2, we estimate effects of homelessness on postpartum maternal and infant health and healthcare utilization. Our longitudinal dataset allows us to explore the timing of exposure, account for preconception health and compare outcomes across different pregnancies for the same person. In Aim 3, we estimate effects of PSH and RRH in this population. We use a difference-in-differences framework to provide the first quantitative estimates of the impact of these interventions on maternal and infant health and racial and ethnic health inequities. Guided by our advisory board members’ lived experience and clinical training, findings will be used to develop intervention studies and inform policy to improve prenatal and postpartum care for birthing people and infants who have experienced homelessness.

NIH Research Projects · FY 2025 · 2025-09

The accumulation of mycotoxins, chemical by-products of fungal growth, is an emerging issue in public health due to their widespread presence in food systems. Mycotoxins contaminate crops worldwide and their prevalence will increase as ecosystems become warmer and wetter. One of the most common mycotoxins, zearalenone (ZEN), derives from Fusarium species and is widely detected in cereal grains, grain-based products, meat, milk, wine, beer, dried fruit, and spices. ZEN and its metabolites bind to estrogen receptors earning their designation as ‘mycoestrogens’. In livestock and experimental models, ZEN exposure dysregulates maternal and offspring hormone signaling, alters gestational weight gain, and disrupts offspring growth and pubertal trajectories. Despite the large and compelling toxicological literature and the near ubiquitous human exposure, alarmingly little is known about ZEN’s impacts on human health. In the first epidemiological study of its kind, we recently observed that higher urinary ZEN concentrations in U.S. pregnant women were associated with sexdependent differences in circulating estrogens in pregnancy, greater gestational weight gain, and altered infant size. These findings have led us to the overarching hypothesis that developmental mycoestrogen exposure disrupts steroidogenic and metabolic activity in humans, leading to sex-specific alterations in child growth. What is now urgently needed are studies that more extensively characterize both prenatal and childhood exposures to ZEN in large, diverse samples with further exploration of mechanistic pathways and extended follow-up into adolescence. Here, we fill those gaps and advance the limited epidemiological research on ZEN by leveraging existing data and biospecimens from TIDES (The Infant Development and the Environment Study), a deeply-phenotyped, multi-site U.S. cohort that recruited pregnant women from 2010-2012. Using existing data and biospecimens from the full TIDES cohort (494 mother-child dyads), we will examine prenatal and childhood exposures to ZEN and its metabolites in relation to (a) steroidogenesis and metabolomics in pregnancy; and (b) child growth from birth through adolescence. This will be the first study to examine the potential health impacts of prenatal and childhood exposure to mycoestrogens in U.S. mothers and children. Leveraging the uniquely suited TIDES cohort, we address national mandates to examine variation by sex and provide sorely needed information on emerging mycoestrogen exposures. We anticipate that results may help identify harms and inform mitigation strategies to reduce exposures as well as efforts to regulate mycoestrogens in the food supply in the U.S. and beyond.

NIH Research Projects · FY 2025 · 2025-09

Halting tuberculosis (TB) transmission by active case finding is challenging, requires substantial resources and is unaffordable in many countries with a high burden of TB. Host-directed therapeutics or prevention of infection (POI) vaccines that prevent Mycobacterium tuberculosis (Mtb) from establishing infection in exposed contacts could be potentially powerful tools to break the transmission cycle of Mtb and accelerate TB elimination. Significant gaps exist in our understanding of the biology of the spectrum of Mtb infection in exposed contacts. A household contact (HHC) study conducted by our group found that the transmissibility of Mtb from the index case was heterogenous using Interferon-Gamma Release Assay (IGRA) and tuberculin skin test (TST) positivity to infer infection. Households (HH) were categorized into High (HT), and Low (LT) transmission groups based on the proportion of HH contacts (HHC) with a positive (IGRA) and/or TST. Mtb strains from index cases of the HT and LT households were designated Mtb-HT and Mtb-LT, respectively. In susceptible mice, Mtb-HT and Mtb-LT strains induced distinct in vivo immunopathological responses. Furthermore, Mtb-HT and Mtb-LT strains induced distinct metabolic reprogramming of THP1 cells (preliminary data). Individuals who remain IGRA negative despite long-term and intense exposure to Mtb, are considered to have either resisted infection or cleared it and are referred to as ‘resisters’. Several immune mechanisms have been associated with resister phenotype, including responses mediated by macrophages, T cells and B cells. In preliminary studies, we found that a significant proportion of IGRA- HHCs were from LT-HH and had evidence of non-canonical antigen-specific T cell (NCAT) activation (measured as increased expression of activation markers) that was interferon (IFN) independent. This suggests that the current binary classification of exposed contacts as IGRA+ or IGRA- does not capture the complexity of the Mtb infection spectrum. Moreover, NCAT activation in IGRA- may be a protective phenotype as most TB arises from IGRA+ individuals. Epidemiological studies have shown a substantial association between human genetic variations and bacterial genotypes and the development of TB. Our overarching hypothesis is that Mtb-HT and Mtb-LT strains are phenotypically and genetically diverse, and the contribution of this inter-strain variability is at least as consequential to infection outcome in exposed individuals as is the contribution of inter-individual variability. Findings from our study will provide insights into mechanisms that regulate resistance to Mtb infection. Identification of mechanisms of resistance may lead to novel approaches for immunomodulatory therapy targeting host macrophage anti-microbial pathways and identifying genomic signatures segregating Mtb-HT and Mtb-LT may provide novel Mtb targets for developing POI vaccines that induce T-cell responses that activate macrophages or “train” the innate immune system to eliminate Mtb.