Emory University

NIH Research Projects · FY 2026 · 2026-05

NMDA receptor regulation of rapid scaling and spinal excitability in fragile X syndrome. Abstract Identifying the mechanisms that control the maturation of network excitability during development will be crucial to understanding how these networks are established with dysregulated activity in cases of neurodevelopmental disorders such as autism spectrum disorder (ASD). We are proposing to study a guiding principle for the maturation of network excitability during neonatal development. We have just recently published work in the chick embryo spinal cord showing that blockade of NMDA receptors triggers rapid compensatory changes in the strength of glutamatergic and GABAergic synapses, referred to as synaptic scaling. This rapid form of synaptic scaling was previously characterized in a very different model system - rodent hippocampal cultures and slices. The observation that rapid scaling has been identified in 2 very different systems illustrates the fundamental importance of this form of plasticity. In the current application we will study rapid scaling in the neonatal mouse spinal cord, as we have preliminary results suggesting this plasticity exists in mouse spinal neurons, and that some inputs are altered more than others (nonuniform). In Aim 1 we will identify which classes of neonatal mouse spinal neurons express AMPAergic (excitatory) and GABAergic (inhibitory) rapid scaling and assess the uniformity of this scaling. We hypothesize that the homeostatic scaling capacity will be correlated with NMDAR content and will impact the excitatory to inhibitory (E/I) balance within the network and therefore maturation of excitability. Interestingly several different autism spectrum disorder (ASD) models experience altered NMDAR function and altered E/I balance. It is therefore reasonable to suggest that NMDA-dependent rapid scaling may indeed be altered in these models of autism, thus changing their excitability. ASD models have significant delays in motor development, yet spinal cord studies in these model systems are surprisingly rare. In Aim 2 we will test the hypothesis that rapid scaling is dependent on NMDAR content and that this is altered in a mouse model of Fragile X Syndrome (FXS), the most common monogenetic cause of ASD. By understanding the mechanisms of homeostatic plasticity during circuit formation, we will better understand the maturation of network excitability in neurodevelopmental disorders like ASD.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY In this exploratory project, our goal is to establish a physiological rodent model of chronic hepaciviral infection subsequently leading to the natural induction and progression of hepatocellular carcinoma (HCC), which can be immensely advantageous in understanding cancer immunobiology and translating future immunotherapies against virus-induced HCC. Our preliminary data using a rodent analog of hepatitis c virus, rat hepacivirus (RHV), highlighted a critical role for B cells for viral clearance during RHV infection. The lack of mature B cells in μMT mice prevented timely clearance of virus, resulting in persistent infection. Notably, persistent RHV infection of μMT mice led to an early elevation of alpha-fetoprotein (AFP) levels in serum, a commonly employed tumor marker for HCC, and subsequent development of HCC at 6-9 months post-infection. The nature of anti-tumoral T cell immunity in mice that develop persistent viremia due to the lack of B cells help is not clearly understood. Whether antigen-specific B cells can support T cell responses directly through antigen presentation or indirectly through local production of IgG or the recruitment of professional antigen presenting cells (e.g., dendritic cells) remains unclear. In this exploratory grant, we propose to use mice with intact B cells that show variable defects in these B cell attributes to elucidate whether the antigen-specific B cells, or B cell-specific antigen presentation or IgG production contribute to viral-induced HCC formation. We will use mice with intact B cells that show variable defects in B cell functions: a) B1-8i mice with a restricted B cell receptor repertoire, b) MHCIIf/fCD19cre conditional knockout mice that lack B-cell-specific antigen presentation, and c) AIDCre mice that lack activation-induced cytidine deaminase, where in B cells fail to undergo class-switch recombination or somatic hypermutation, with no IgG production. (Aim 1) Using these mice strains lacking several B cell attributes (e.g., antigen specificity, antigen presentation, and IgG production), we will elucidate how it influences tumor microenvironment, the progression of HCC tumors, and impacts anti-viral and anti-tumoral T cell responses. (Aim 2) To identify whether IgG antibodies are the effector functions of B cell-mediated clearance of viral persistence and HCC development, we will first unravel the viral target of IgG and passively transfer viral-specific IgG antibodies from RHV-infected WT mice into AIDCre mice during the longitudinal progression of tumor. If successful, our proposed mice strains developing human analogous virus-induced HCC progression will be exceptionally beneficial over artificial models of tumor induction in understanding B cell cancer immunobiology and informing future IgG based immunotherapies against viral-induced HCC.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The ability to non-invasively measure the mutated form of cytosolic NADP+- dependent isocitrate dehydrogenase (IDH1) activity using positron emission tomography (PET) will transform the clinical management of low-grade glioma and secondary glioblastoma multiforme (GBM). IDH1 mutations occur in more than 70% low-grade glioma and up to 85% secondary GBM. While IDH1 mutations, most commonly IDH1-R132H, are associated with significantly improved overall and progression-free survival compared to wild-type IDH1 gliomas, these mutations also profoundly alter cellular metabolism, influencing the tumor immunometabolic environment and contributing to malignant progression. Therefore, non-invasive imaging of IDH1 mutational status is paramount for the clinical diagnosis, characterization, and treatment of low- grade glioma and secondary GBM. Furthermore, the current development and translation of the IDH mutation targeted treatment with IDH1-R132H inhibitors highly depend on availability of highly sensitive and specific imaging methods to measure drug-target engagement and drug occupancy, and monitoring therapeutic efficacy without repeated biopsy. Given that there is no IDH mutation targeted imaging tracer available, the proposed exploratory R21 project aims to develop an IDH1-R132H-specific PET tracer by making 18F-AG-881 and 18F- heteroaromatic derivatives of AG-881 or vorasidenib, an IDH1-R132H inhibitor currently in clinical trial for treatment of low-grade gliomas harboring IDH1 or IDH2 mutations. In this project, we will synthesize six rationally designed 19F-heteroaromatic AG-881 analogs and evaluating their IC50 properties in IDH1-R132H transfected and IDH-WT glioma cells in vitro. Based on these results, we will develop and optimize an 18F-radiolabeling approach for the most promising probe candidates. The uptake and target engagement of the resulting ¹⁸F- labeled IDH1-R132H PET tracer candidates will then be assessed in IDH1-R132H expressing cells. To evaluate blood-brain barrier permeability, we will measure the uptake and efflux activity of each candidate. The lead 18F- IDH1-R132H probe will be selected based on: 1) the lowest IC50=<10 nM at IDH1-R132H; 2) sensitivity ratio of > 10:1 IDH1-R132H:IDRH-WT; 3) standardized uptake value (SUV) >3 in the brain; 4) lowest P-gp activity; and 5) brain clearance halftime of ≥ 30 min. We will then test and evaluate the developed probe in vivo through microPET imaging to quantify IDH1-R132H expression levels in mice bearing orthotopic tumors carrying IDH1- R132H. Tracer uptake and PET-derived measurement of the IDH1-R132H expression level will be validated through immunohistochemical analysis of excised tumor sections and correlated with ex vivo magnetic resonance measurements of D-2-Hydroxyglutarate (2-HG), a product of the IDH1-R132H mutant, in the tumor tissue. We anticipate the developed IDH1-R132H-specific PET tracer will enable: 1) confirmation of IDH1-R132H mutation status with spatial resolution not achievable through biopsy; 2) quantitative assessment of IDH1-R132H expression levels in vivo, and 3) valuation of the effectiveness of IDH1-mutant–targeted therapies and agents.

NIH Research Projects · FY 2026 · 2026-05

The overall goal of this proposal is to develop a vaccination strategy that induces strong and durable humoral and cellular immunity against HIV, providing long-term protection even with low neutralizing antibody (Ab) responses using DNA-LNP technology. Developing an effective HIV-1 vaccine has been an elusive goal for over four decades. An ideal HIV vaccine should generate a potent and broadly cross-reactive neutralizing antibody response (bnAb) that remains at high titers for many years. Native-like trimeric HIV envelope (Env) gp140 immunogens, such as SOSIP, NFL, and UFO, have significantly advanced the field by eliciting autologous nAbs; however, they do not induce an antibody response with neutralization breadth. We and others have shown that a serum neutralization titer of around 300 or higher is necessary for nearly complete protection in non-human primates (NHPs). These findings underscore the importance of developing vaccination methods that maintain persistent nAb levels at or above this threshold. Besides nAbs, CD8 T cells—especially tissue-resident memory T cells—are crucial for protection against HIV. Our recent studies indicate that adding a T cell-inducing vaccine to an nAb-inducing vaccine can significantly lower the neutralization titer threshold needed for long-term protection against intravaginal SHIV challenges, bringing it below detectable levels. Therefore, we hypothesize that vaccine approaches that induce strong, lasting CD8 T cell responses, along with neutralizing antibodies, will improve protection against HIV—even when serum neutralizing antibody levels are low. In ongoing studies, we compared the immunogenicity of mRNA-LNPs with DNA-LNPs expressing SIV Gag in rhesus macaques (RMs). We observed that DNA-LNPs elicit 25-fold higher levels of Gag-specific CD8 T cell responses compared to mRNA-LNPs. Moreover, the CD8 T cells induced by the DNA-LNP vaccine were durable, showing only about 2- fold contraction over four months post-boost. The DNA-LNP vaccines also produced strong Gag-specific antibody responses that showed minimal contraction over several months. Notably, this high level of immunogenicity was achieved with just 100 μg of DNA in RMs—significantly less than the 3 mg of naked DNA typically used in NHPs and humans. These data demonstrate that DNA-LNP vaccines induce potent and lasting CD8 T cell and antibody responses, supporting further testing of the immunogenicity and efficacy of this approach in providing durable protection against HIV in NHPs. This proposal has two specific aims. Aim 1 will assess the immunogenicity and durability of DNA-LNP vaccines and optimize envelope immunogens. We will compare three DNA-LNP vaccines and select one based on immunogenicity and durability of humoral and cellular immunity. Aim 2 will determine the efficacy of the optimized DNA-LNP vaccine for protection against intravaginal tier 2 SHIV challenges. By the end of these studies, we aim to develop a novel HIV vaccination strategy that elicits durable cellular and humoral immunity, providing long-term protection.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Approximately 30% of patients with epilepsy have treatment-resistant (refractory) seizures, presenting a major clinical challenge and burden. The acquired and genetic forms of epilepsy represent the two major classes of epilepsy, and these arise mainly from neurological insults and genetic mutations, respectively. Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy, and mesial temporal lobe epilepsy (MTLE) is the most common subtype of TLE. Dravet syndrome (DS), the most common form of genetic epilepsy, is a catastrophic pediatric disorder which is most frequently caused by mutations in the SCN1A voltage-gated sodium channel. The mechanisms that contribute to the eventual development of seizures and associated comorbidities in MTLE and DS are still incompletely understood, and further research on the cellular and molecular changes that underlie these disorders is necessary in order to facilitate the development of improved treatments. Extracellular vesicles (EVs) are small, membranous particles that are naturally released by cells. EVs play an important role in intercellular communication and have been shown to possess anti-inflammatory and neuroprotective properties. Accordingly, the administration of EVs isolated from healthy, non-pathogenic cellular sources such as mesenchymal stem cells (MSEs) and neural stem cells have been demonstrated to reduce pathology in models of MTLE, stroke, TBI, and neurodegenerative disorders. Our preliminary data also suggests that endogenously-released EVs in the brain (i.e. brain derived EVs or BDEVs) from naïve wild-type mice have anti-inflammatory and cell protective properties. However, in certain disease states, BDEVs can become dysregulated and contribute to neuroinflammation and disease pathology. Little is known about the role of BDEVs (i.e., protective versus pathogenic) during the development of epilepsy. To date, only two studies have examined BDEVs in rodent MTLE models. While both studies identified changes in the expression of BDEV miRNAs following status epilepticus, neither study examined whether the functional properties of the BDEVs were altered. Furthermore, whether BDEVs are altered in genetic epilepsies and contribute to disease development is completely unknown. Hence, the objective of this exploratory R21 proposal is to establish whether BDEV properties are altered in mouse models of MTLE and DS. Importantly, the analysis of two models with distinct epileptogenic mechanisms will establish conserved and epilepsy subtype-specific BDEV contributions. The data generated in this study will provide new information on the role of BDEVs in the development of acquired and genetic forms of epilepsy, and may potentially identify novel targets for therapeutic intervention.

NIH Research Projects · FY 2026 · 2026-05

The purpose of this K23 Career Development Award is to support the applicant in becoming an independent investigator with expertise in implementation science, to study strategies that increase the uptake and use of evidence-based autism services, and to measure the system-level impact of these efforts. Building on the applicant’s existing background in autism health services research and mixed methods, the proposed career development plan will achieve this long-term goal through a combination of implementation science training program activities, coursework, workshops, seminars, and mentored research. These activities will serve as learning vehicles for new skills and knowledge across the following three short-term training goals: 1.) learn to use human-centered design with embedded community-engaged research methods to improve acceptability and usability of interventions and implementation strategies; 2.) gain expertise in the design and conduct of pragmatic, hybrid clinical trials that target effectiveness and implementation outcomes; 3.) learn to evaluate implementation strategies and interventions at the system-level. Training in these areas will support the applicant’s achievement of the following research aims: 1.) adapt the ECHO Autism: STAT Early Diagnosis (EDx) implementation strategy to utilize a biomarker-based diagnostic tool for patients 16-to 30-months old, in a manner that maximizes acceptability and usability; 2.) examine feasibility and acceptability of testing ECHO Autism: STAT EDx vs. ECHO Autism: Technology-Enhanced EDx through a pilot cluster randomized hybrid type 3 trial; 3.) explore differences in time from autism screen to diagnostic ascertainment between 3 groups of patients with positive autism screening results across a large network of pediatric primary care sites: those served by PCPs assigned to each of the two pilot study conditions, and those from all other network sites that did not enroll in the pilot. These research and training goals will be carried out under the co-primary mentorship of Dr. Lawrence Scahill, an expert in autism clinical trials, and Dr. Sarabeth Broder-Fingert, an expert in applications of implementation science to autism health services research; and co-mentorship from Dr. John Constantino, an expert in biomarker-based and environmental influences of autism as well as system-level change to improve mental and behavioral health care. These career development and research activities will occur within a robust infrastructure for training and community-engaged autism research, leveraging strengths of Emory University School of Medicine, Emory University Rollins School of Public Health, the Marcus Autism Center, Project ECHO, and a network of over 175 pediatric primary care practices across Georgia. This K23 proposal is aligned with the NIMH’s Strategic Plan Goal 4: to advance mental health services to strengthen public health. With further training, the applicant is poised to begin a trajectory of work as an independent investigator to promote accessible, early autism services, ultimately improving outcomes for children.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Most patients diagnosed with acute myeloid leukemia (AML) die of the disease due to development of resistance to existing chemotherapy or targeted therapy. This problem underscores the compelling need for understanding of relapse emergence mechanisms and identification of effective targeted strategies to overcome leukemia relapse. Recently, by using dynamic BH3 profiling that measures rapid change in drug-induced apoptotic signaling, we identified drugs that can overcome resistance to venetoclax, a selective BCL-2 inhibitor and active drug in leukemia (Bhatt et al, Cancer Cell 2020). Through mechanistic studies using patient derived xenograft (PDX) models, we next found venetoclax resistance emergence is accompanied by reduced sensitivity of mitochondria to apoptotic signaling mechanisms. Surprisingly, we found that resistance to disparate, narrowly-targeted agents in distinct PDX models was consistently accompanied by broad resistance to a wide variety of drugs, indicative of multi-resistance phenotype at relapse (Olesinski et al, Blood Cancer Discovery, 2024). We then reported that selection for reduced mitochondrial priming drives multi-drug resistance phenotype at relapse. By building upon these findings, we hypothesize that stable acquired resistance emerges from drug-tolerant leukemic persister cells and that the persister cells can be targeted by exploiting mitochondrial apoptotic signaling mechanisms. To address this, we propose to utilize Watermelon 2.0 library an innovative lentiviral construct that contains both an expressed barcode, and an inducible histone-2B (H2B-mCherry) florescent dilution system, to trace in vivo clonal evolution. In Aim 1, we will look for an evidence of both genetic and non- genetic modes of clonal evolution of resistance using high-complexity DNA barcoding, proliferative index, and whole genome studies. In Aim 2, we will identify cellular states that contribute to persister development by single-cell transcriptomics and define persister memory by chromatin accessibility and identify persister specific dependencies by whole-genome CRISPR KO screen. In Aim 3, we will determine whether relapsing clone carries chemical vulnerabilities observed in the pre-existing clone or do they acquire new pathway dependencies using DBP. We will then determine whether drugs targeting pre-existing and novel pathway dependencies, either alone or in combination are sufficient to prevent AML relapse.

NIH Research Projects · FY 2026 · 2026-05

Summary. Established in 2011, the Southeastern Pediatric Research Conference has become a leading regional meeting that brings together researchers, clinicians, students, trainees and other healthcare professionals dedicated to advancing pediatric science and making an impact on child health. Co-hosted by Emory University Department of Pediatrics, Children’s Healthcare of Atlanta, Georgia Institute of Technology, and Morehouse School of Medicine, the conference serves as fertile ground for promoting cross-institutional collaboration and highlighting innovative research focused on improving pediatric conditions. The 2026 conference will be held on August 28 at the Georgia Aquarium and will commemorate 15 years of fostering scientific exchange and professional development in pediatric research. The theme of the next conference is “Bench to Bedside and Beyond: Transforming Our Research to Impact Children in Our Communities”. This theme reflects the conference’s commitment to supporting the continuum of research from basic sciences to community-based research. The program for this one-day event includes keynote lectures by prominent invited speakers, rapid-fire presentations by trainees, students and young investigators, interactive poster sessions, and dedicated time for networking and mentoring opportunities With over 540 attendees and more than 200 abstracts in 2025, the conference continues to grow. The scientific programming of the meeting includes multiple NICHD priority areas, including child development and behavior, developmental biology and congenital anomalies, maternal and pediatric infectious diseases, pediatric growth and nutrition, pharmacology, and intellectual and developmental disabilities. Considering the strong interest of the broader research community, as well as the lack of comparable conferences across the nation, we propose a five-year plan to expand the reach of the conference to accommodate the growth and interest in this destination child health research event while keeping registration fees relatively low. With NICHD’s R13 support, we will be able to sustainably implement this expansion as a premier forum for promoting child health research and training and connecting the next generation of pediatric researchers.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ ABSTRACT Antibiotic resistance is a growing global threat with nearly three million infections associated with antibiotic- resistant bacteria and >35,000 annual deaths from such infections in the US alone. Among these threats, Pseudomonas aeruginosa poses a serious challenge to hospitalized (e.g., those that are intubated and mechanically ventilated), post-surgical and immunocompromised individuals (e.g., in cancer and HIV), as well as those with lung infections due to genetic disorders such as Cystic Fibrosis. A major problem in treating P. aeruginosa, and many other Gram-negative infections, is its high intrinsic resistance to antibiotics, including through the action of multiple genome-encoded efflux systems. P. aeruginosa encodes a total of 12 efflux pumps of the Resistance-Nodulation-Division (RND) family, at least four of which contribute to intrinsic resistance to many clinically important antibiotics such as aminoglycosides. RND efflux systems are tripartite protein complexes, e.g., P. aeruginosa MexXY-OprM, comprising an inner membrane-embedded transporter protein (e.g., MexY), a periplasmic adaptor protein (PAP; e.g., MexX) and an outer membrane protein (OMP; e.g., OprM). P. aeruginosa RND pumps have overlapping but distinct antibiotic substrate profiles with the MexXY transporter-PAP complex being unique in its ability to efflux aminoglycosides. Furthermore, some transporter- PAP complexes have a specific OMP partner, while others combine with more than one (e.g., MexXY binds OprM and OprA). Published and preliminary data from our lab suggest that MexY has multiple potential entry sites for antibiotic substrate uptake. However, the paths followed by substrates through MexY via MexX to the OMP and the consequences of different OMP association with the transporter-PAP complex on the efflux process are unknown. For this reason, detailed structural and functional studies are urgently needed to define efflux pathways will enable inhibitor design with better target specificity and hence decreased off-target effects. In this project, I will test my overall hypothesis that efflux substrates follow a specific pathway through the assembled RND efflux system and that the efflux pathway(s) depend on the outer membrane protein identity. I will test this hypothesis in two complementary Specific Aims. Aim 1–I will determine the pathway through which antibiotic substrates are translocated out of the RND transporter protein MexY using molecular dynamics simulations complemented with functional assays and high-resolution structural studies. Aim 2–I will define the interdependency between the OMP and the antibiotic substrate efflux pathway within MexY using a combination of molecular dynamics simulations, functional assays, and high-resolution structural studies. Defining the efflux pathways used by antibiotic substrates will enhance our understanding of how the MexXY-OprM/A pumps confer high levels of aminoglycoside antibiotic resistance. Such insights will set the stage for future structure- and computational-guided development efflux pump inhibitors while establishing protocols that can be used to study other efflux pumps that contribute to resistance to other antibiotic classes.

NIH Research Projects · FY 2026 · 2026-05

Numerous studies show that it is not individual cells but rather collective packs of invasive cells that metastasize. These collective invasion packs are observed histologically in patient tumors, mouse models, and 3D cultures. In many cases, a hierarchical group of leader and follower cells is observed, where the invasive leader cell at the tip of the invading pack guides the followers forward. Despite their prevalence, research generally focuses on how individual cells invade or studies treat cells as a homogenous group, thereby lacking the resolution to investigate subpopulations. Using an image-guided genomics approach we developed, we published that collective invading non-small cell lung cancer (NSCLC) subpopulations have differential genetic mutations and epigenetic profiles that support distinct metabolisms. Our preliminary data show that, while leader cells alone metastasize, these disseminated leaders primarily form non-proliferative micrometastatic lesions positive for markers of endoplasmic reticulum (ER) stress and cell cycle inhibition, suggestive of a dormancy phenotype. However, the mixing of leaders and followers within the primary tumor results in actively proliferating macrometastatic lesions. This raises the possibility that cell:cell cooperation between disseminated subpopulations is required to transition from micro- to macrometastatic disease. Our in vitro studies suggest a mechanistic link between oxygen tension, glycolysis, ER stress and ER-associated protein degradation (ERAD) in regulating this leader cell quiescence. We found that the glycolytic enzyme glucose 6-phosphate isomerase (GPI), which catalyzes the interconversion of glucose 6-phosphate and fructose 6-phosphate, is secreted in an oxygen (O2)-dependent manner, lowly expressed in highly invasive leader cells, and can rescue low oxygen induced stress in leaders. Based upon these data, we will test the overarching hypothesis that a GPI cargo exchange gatekeeps metabolic flexibility and ERAD-dependent disseminated leader cell dormancy to perpetuate tumor cell growth and promote tumor progression. We propose to define how a metastatic, dormant subpopulation of invasive cells relies on inter-subpopulation cooperation to activate and proliferate at the metastatic site, probe a model that positions GPI centrally within a metastatic dormancy axis, and deconstruct a new O2-dependent glycolytic secretory pathway that modulates ER-associated stress. These studies will have significant impact on resolving the fundamental mechanisms at the intersection of metabolic heterogeneity and cell:cell communication in collective invasion and metastasis.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Antibiotic resistance is a global public health problem that has been aggravated in the last decades by the emergence and spread of multidrug-resistant microorganisms. Each year, it is estimated that resistant pathogens are responsible for more than 99,000 deaths in the United States. Particularly problematic is the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp), bacteria capable of ‘escaping’ the action of antibiotics and which represent new paradigms in pathogenesis, transmission, and resistance. Together with Escherichia coli, the ESKAPE group are responsible for most life-threatening bacterial infections in health care facilities. These bacteria exhibit an intrinsic low susceptibility to multiple antibiotics, as well as an overwhelming capacity to develop resistance via mutations. The ability to predict the mechanisms and genetic basis of antibiotic resistance is paramount to establishing new treatment protocols to fight these bacterial infections. To elucidate the evolutionary trajectories to antibiotic resistance in S. aureus, P. aeruginosa, and E. coli, and how the immune system changes these trajectories, experimental evolution assays will be performed in vivo using the larvae of Galleria mellonella (a lepidopteran model used for the study of infections). These Adaptive Laboratory Evolution experiments will be conducted in the presence of the antibiotics used clinically to treat infections caused by these bacteria. At multiple time-points and at the end of the experiment, the genetic basis of resistance and the order of appearance of these genetic variants will be characterized to determine the contribution of each mutation to the observed resistance. Furthermore, the fitness cost and the cross-resistance and collateral susceptibility of these mutations will be identified (Aim 1). In view of treatment failures arising from antibiotic resistance, novel strategies are needed to deal with these infections. Hence, there has been a resurgence of interest in the use of lytic bacteriophages for treating bacterial infections: phage therapy. Currently, phage therapy is only used as a last line therapy for patients for which no other treatment has been successful. Often, these patients are being treated with multiple antibiotics both before and during phage treatment. For phage therapy to become commonly employed, these bacterial viruses must be used in conjunction with antibiotics; and, moreover, we must know how these viruses, antibiotics, and the host’s immune system interact. To design and evaluate protocols based on the combination of antibiotics and lytic phages to treat bacterial infections, the research proposed will develop and analyze the properties of mathematical and computer-simulation models, estimate the parameters of these models in vitro and in vivo, analyze the properties of these models using G. mellonella, to ultimately determine the optimal combinations of antibiotics and lytic phages for the treatment of infections with S. aureus (Aim 2).

NIH Research Projects · FY 2026 · 2026-04

Project Summary Parkinson’s disease (PD) is primarily characterized by symptoms caused by loss of midbrain dopamine (DA) cells that modulate the function of striatal neurons. DA replacement with L-Dopa is effective to control symptoms for some time, but as disease progresses the overall efficacy of L-Dopa declines and, as a result, patients suffer increasing disability. The mechanisms underlying this evolution of DAergic therapy are poorly understood, although there is evidence for maladaptive plasticity of striatal projection neurons (SPNs). Such maladaptive plasticity involves changes in DA signaling pathways that are mediated by the second messengers, i.e., cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). A critical regulation of cGMP and cAMP levels derives from their catabolic enzymes, the phosphodiesterases (PDEs). However, how these cyclic nucleotides are regulated in direct and indirect SPNs remains unknown. These knowledge gaps are critical limitations to unveil the mechanisms for altered SPN responses to long-term DA replacement therapy. This new study is focused on the dysregulation of cyclic nucleotides that develop in SPN subtypes comparing models of early- and late-stage PD. The project includes three specific aims to determine the impact of increasing cGMP and cAMP levels using specific PDE inhibitors and comparing animal models of different disease stages. Studies include analysis of motor behavior, cellular activity with various electrophysiologic techniques, and parameters of molecular changes in the brain, such as the expression of PDEs. In specific aim 1, we will use rodent (rat) models and focus on behavioral analysis after selection of appropriate pharmacological tools for manipulating nucleotide levels with high specificity. In specific aim 2, we will use the same models to analyze the drug impact on SPN function using transgenic rats for cell resolution. In specific aim 3, we will examine the effects of PDE inhibitors in primate models assessing both behavioral and physiological outcomes. In addition, we will analyze the striatal PDE expression changes developed in the late-stage PD. Our approach includes the use of innovative animal models, pharmacological analysis, modern technologies (optogenetics), multiple RNA in situ hybridization analysis, and a combination of rodent and primate studies to generate refined data with translational application. These studies will shed light on the mechanisms underlying deficient and altered SPN responses to DA. Furthermore, we expect to identify molecular targets for developing new therapeutic strategies that can improve the life quality of patients with PD.

NIH Research Projects · FY 2026 · 2026-04

Abstract Bacterial resistance to antibiotics is an escalating crisis in healthcare that threatens to fundamentally alter modern medicine. There are many distinct mechanisms of antibiotic resistance in bacteria, but increased production of multidrug efflux pumps is a common response among pathogenic bacteria to remove drugs from the cell. The Resistance-Nodulation-Division (RND) efflux pump superfamily is broadly distributed among Gram- negative pathogenic bacteria and contributes extensively to clinical resistance. The important opportunistic pathogen Pseudomonas aeruginosa encodes multiple RND efflux systems, at least four of which contribute to its intrinsic multi-drug resistance. A major efflux pump in P. aeruginosa is MexXY-OprM and it is the only efflux pump that can export aminoglycosides, an antibiotic that is clinically relevant in the treatment of bacterial infections. MexXY is regulated by the expression of the PA5471 operon that encodes for a regulatory leader peptide, PA5471.1, and the PA5471 protein. The PA5471.1 leader peptide and aminoglycoside exposure controls the expression of PA5471. The SuhB protein, typically known to interact with RNA polymerase as an integral part of the antitermination complex for ribosomal RNA biosynthesis in E. coli, is also involved in this regulation in the absence of aminoglycosides by preventing both ribosome stalling and protein production of PA5471. However, the molecular and structural bases of this novel gene regulation are unknown. My hypothesis is that aminoglycoside binding to the ribosome in the presence of the PA5471.1 leader peptide inhibits SuhB function and causes ribosome stalling to confer downstream gene expression of PA5471, suggesting a novel mode of gene regulation. In Aim 1, I will use reporter assays to determine the regions in the PA5471.1 leader peptide and the downstream intergenic region between PA5471.1 and PA5471 that are important for PA5471 production and thus MexXY production. I will also identify PA5471.1 leader peptide amino acids important for ribosome stalling using biochemical assays. Lastly, I will determine the structural basis of aminoglycoside-mediated ribosomal stalling in the context of actively translating PA5471.1 by cryogenic-electron microscopy. In Aim 2, I will determine the important SuhB residues for the regulation of PA5471 using reporter and biochemical assays to test whether SuhB functions as a transcription or translation factor. Finally, I will determine the structural basis of SuhB interaction with the ribosome by cryogenic-electron microscopy. Collectively, my results will reveal important aspects of P. aeruginosa antibiotic-mediated gene regulation and intrinsic antibiotic resistance. These studies will provide the foundation to identify new targets for novel antibiotic drug development to combat the increasing antibiotic resistance in P. aeruginosa.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT OF PROPOSED RESEARCH Antiviral nucleoside analogs have proven effective in treating chronic hepatitis B (CHB) and improving the survival and quality of life for those living with CHB. However, a cure remains elusive. Currently, individuals with CHB, including those co-infected with HIV, require lifelong oral medication to suppress the virus to undetectable levels. Challenges related to medical adherence and limited access to drugs persist, underscoring the need for long-acting release formulations. Capsid assembly modulators (CAMs) represent a promising class of antivirals that disrupt the HBV capsid assembly process, preventing the encapsidation of pregenomic RNA and inhibiting viral replication. Furthermore, at higher concentrations, CAMs impede the transcription and de novo formation of covalently closed circular DNA (cccDNA) in the early stages of infection. ALG-001075 is a proprietary, novel, pan-genotypic CAM with sub-nanomolar in vitro potency. Its oral prodrug, ALG-000184, is currently being evaluated in clinical trials involving individuals with CHB, where it has shown unprecedented reductions in HBV DNA, RNA, and viral antigens, as well as superior HBV DNA reduction compared to nucleoside analogs. As the active metabolite of ALG-000184, the exceptional potency, dual anti-HBV mechanism, and safety profile position ALG-001075 as a strong candidate for long-acting regimens. This study aims to develop a biodegradable and biocompatible nanoparticle (NP) injectable sterile formulation that encapsulates ALG-001075 for prolonged release. This sustained drug release can extend the dosing interval from daily to monthly or even longer, providing significant benefits for individuals living with CHB or co-infected with HIV/HBV. Enhanced drug efficacy due to improved adherence and reduced costs will be particularly beneficial in areas lacking birth dose vaccination or in low-resource settings, where HBV carrier rates are extremely high. The specific aims are: 1) To formulate and optimize an NP delivery system for ALG-001075 that achieves extended in vitro release for at least one month (R61 phase); 2) To determine the pharmacokinetics of ALG-001075 following NP delivery (R61 phase); 3) To evaluate the in vivo antiviral efficacy of long-acting ALG-001075 in HBV mouse models (R61 & R33 phases); 4) To manufacture the drug substance and drug product to facilitate toxicology studies (R33 phase); 5) To assess the in vivo safety of long-acting ALG-001075 (R33 phase). To achieve these goals, we will initially explore the encapsulation of ALG-001075 in biodegradable polymeric NPs or lipid NPs. Formulations will be evaluated in vitro to assess release kinetics and stability and in rodents to establish exposure durability and efficacy. In the R33 phase, we will utilize existing procedures for synthesizing ALG-001075 to manufacture the drug substance and prepare a long-acting formulation that can proceed to IND-enabling toxicology studies. With the IND-directed product development strategy, we anticipate that at least one NP design will meet the requirements and advance to IND filing.

NIH Research Projects · FY 2026 · 2026-04

Project summary Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited therapeutic options and striking sex-based differences in immune responses. Despite the transformative impact of immune checkpoint inhibitors (ICI) in oncology, their efficacy in PDAC is notably poor. Our research reveals that the vasoactive intestinal polypeptide (VIP) receptor (VPAC) acts as a novel immune checkpoint that suppresses macrophage phagocytosis and adaptive anti-tumor immunity. Notably, VPAC blockade enhances macrophage-mediated tumor control in female PDAC models, but not in males. Whereas androgen signaling suppresses macrophage-mediated immunity in males. Androgen receptor blockade overcomes this and sensitizes VPAC antagonist response in male PDAC models. Building on these insights, we propose a sex- specific approach to reinvigorate the PDAC immune microenvironment by targeting VIP receptor 1 (VPAC1) in females and combining androgen receptor (AR) inhibition with VPAC blockade in males. Thus, our central hypothesis is that activating macrophage phagocytosis by targeting immune checkpoints or androgen receptor (AR) promotes an immune-permissive TME, enhances ICI responses and suppresses PDAC progression. We aim to: Aim 1: Define the sex-specific differences in macrophages regulating anti-tumor immunity against PDAC. We will elucidate how VPAC1 in females and AR/VPAC1 cooperation in males contribute to PDAC immune evasion. By leveraging multiplex fluorescence microscopy, single-cell RNA sequencing (scRNAseq), and functional assays, we will characterize macrophage-T cell interactions and assess the impact of VPAC1 and AR inhibition on tumor immunity. Aim 2: Enhance anti-tumor immune responses by combining VPAC blockade with macrophage- checkpoint inhibitors. We will evaluate the therapeutic potential of combining VPAC1/PD-1 blockade with TIM3 inhibition to amplify macrophage-mediated anti-tumor immunity in both sexes. Our murine PDAC models and mechanistic studies will determine the efficacy and underlying mechanisms of this approach. This project is highly innovative, introducing VPAC1 as a novel macrophage phagocytosis checkpoint and defining its role in sex-specific immunosuppression. Our strategy holds significant translational potential to inform precision immunotherapy and advance clinical interventions for PDAC patients. By addressing the profound sex disparities in immune response, our findings could reshape immunotherapeutic paradigms and improve survival outcomes for both male and female PDAC patients.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Clonal hematopoiesis (CH) is an age-related condition affecting over 20% of individuals aged 70 and older. While CH mutations are known to increase the risk of myeloid malignancies, growing evidence suggests they also contribute to lung cancer development by promoting immune suppression. However, the mechanisms linking CH-driven immunosuppression to tumor development remain poorly understood. This study aims to define how CH mutations drive non-small cell lung cancer (NSCLC) by fostering an immunosuppressive tumor microenvironment, with a specific focus on regulatory B cells (Bregs) and their interactions with myeloid-derived suppressor cells (MDSCs) and T cells. We further hypothesize that targeting IL-1β and Breg signaling can overcome CH-mediated immune suppression and enhance PD-1 blockade efficacy. To test this hypothesis, we will employ murine models of aged Tet2-deficient hematopoiesis, including orthotopic lung tumor models and bone marrow transplantation (BMT) approaches, to investigate how CH mutations promote tumor growth and suppress anti-tumor immunity. We will further evaluate the therapeutic potential of targeting IL-1β and Bregs to disrupt CH-driven immune suppression and improve PD-1 blockade efficacy in NSCLC. Lastly, to translate our findings to the clinic, we will assess the clinical impact of CH mutations on early- stage NSCLC outcomes and profile the immune microenvironment of stage IB (tumor sections) and stage II–IIIA (PBMCs) NSCLC patients using spatial transcriptomics and CITE-seq, defining CH-associated immune alterations predictive of immunotherapy response and disease recurrence. This study identifies novel immunosuppressive populations and their immune crosstalk in CH-driven lung cancer, establishing the first mechanistic link between age-related hematopoiesis and tumor immune evasion. By integrating preclinical models, patient immune profiling, and translational immunotherapy approaches, our findings will provide a new conceptual framework for CH-driven lung cancer progression. This work has the potential to inform biomarker-driven patient stratification and guide the development of targeted combination immunotherapies for CH-associated tumors.

NIH Research Projects · FY 2026 · 2026-04

Project Summary / Abstract Alzheimer's disease (AD) is a devastating dementia with enormous societal burden. Despite recent advances in the development of AD biomarkers and anti-A antibodies as disease-targeting therapies, AD remains challenging to treat, highlighting the urgent need for new biomarkers and targets to improve AD diagnosis and treatment. The goal of this project is to perform innovative research to discover glycosylation-based disease processes and identify glyco-biomarkers and targets for improving AD diagnosis, prognosis, and intervention. Glycosylation is the most prevalent and complex form of protein modification which produces a wide variety of glycosylated proteoforms or glycoforms to control many biological processes, including synaptic function and brain homeostasis. The prevalent localization of glycoproteins and glycoforms in extracellular space and cell surface makes them an attractive source of disease biomarkers and drug targets. Recent evidence obtained by our group and others indicates a link between altered protein glycosylation and AD pathogenesis. However, current knowledge of system-wide changes in protein glycoforms and glycan modifications in AD is limited, and the potential impact of aberrant glycosylation on the etiology of AD and biomarker discovery remain underexplored. The proposed project will address the gap in knowledge and test the novel hypothesis that glycoproteostasis dysregulation and glycoform alterations are critically involved in AD development and progression. We have recently established an innovative platform that integrates intact glycopeptide-based quantitative glycoproteomics and systems biology for large-scale, in-depth analysis of protein glycoforms and site-specific glycan modifications in human patient specimens. We will perform experiments using this transformative platform to elucidate brain glycoproteome alterations in AD and uncover disease-associated targets, networks, and pathways. In addition, we will perform proteome-wide glycoform profiling studies of cerebrospinal fluid and blood specimens from AD and control cases to identify glyco-biomarkers reflective of diverse AD pathophysiology at different disease stages for timely diagnosis and monitoring disease progression. Successful completion of the proposed research will generate new insights into AD pathogenic mechanisms, provide novel biomarkers for AD diagnosis and prognosis, and pave the way forward for developing glycosylation-based therapies to combat this devastating disease.

NIH Research Projects · FY 2026 · 2026-04

Posttraumatic stress disorder (PTSD) is a debilitating mental health condition that disproportionately affects women, particularly those from underserved populations who face higher rates of trauma exposure. PTSD is associated with trauma-related hyperarousal (TRH), which is characterized by increased psychophysiological hyperarousal, including exacerbated fear-potentiated startle, deficits in fear extinction, and increased skin conductance response to trauma reminders. Despite evidence perimenopausal women exhibit peak PTSD prevalence rates and greater symptom severity compared to younger, reproductive-aged women, the biological mechanisms underlying this increased vulnerability to the psychological consequences of hormonal variation remain unclear. The current study aims to investigate the role of the endocannabinoid system, specifically anandamide (AEA), in modulating the severity of TRH during the menopause transition in Black women. The proposed research will test the hypothesis that lower AEA concentrations over the menopause transition will be associated with decreased estradiol concentrations and increased TRH. We will employ a combination of psychological assessments, fear conditioning paradigms, and biological measures to provide a comprehensive understanding of the mechanisms driving TRH exacerbation during perimenopause. The findings from this research have the potential to inform the development of targeted interventions for trauma-exposed women during this critical period of vulnerability. In addition, the F32 fellowship under the guidance of a distinguished mentoring team will provide the applicant with essential training in clinical and translational women's health research, neuroendocrinology, psychophysiology, advanced statistical methods, and scientific communication. This training will be crucial for the applicant's career development as an independent researcher focused on investigating the impact of trauma on women's health across the lifespan, particularly in underserved populations who suffer disproportionately from the adverse health impacts of trauma exposure.

NIH Research Projects · FY 2026 · 2026-04

SUMMARY Trace metal nutrients are essential for fundamental biological processes like cell signaling, metabolism, and survival. However, the absorption of heavy metals through food, water, and air disrupts these critical functions, posing a significant threat to human health. Maintenance of physiological function requires control of metal homeostasis, which involves tight regulation of adequate availability of essential trace metals while minimizing accumulation of toxic heavy metals. Controlling this delicate balance is vital to preserve cellular function and prevent disease. Despite its central importance, our understanding of metal homeostatic systems is limited. A major gap in understanding lies in the involvement of small molecule thiols in metal disposition, despite acknowledgement that abundant, endogenous thiols are engaged in such activities. A new opportunity to study these interactions with metal homeostasis has presented in our recent discovery of phytochelatins (PyCs) in human samples. PyCs are short, thiol-containing peptides produced in plants, where they act as potent metal chelators. PyCs are ubiquitous in the diets, but their presence and influence on human metal homeostasis was only recently discovered. We hypothesize that dietary PyCs are key regulators of human metal homeostasis. Testing this hypothesis from multiple angles will provide critical opportunities to address significant gaps in our understanding of small molecule regulation of metal dynamics. This research not only uncovers a previously unrecognized class of molecules involved in metal homeostasis but also opens new avenues to develop dietary interventions for modifying nutrient bioavailability and excretion of toxic heavy metals, with implications for preventing and mitigating metal-associated diseases. The proposed project will explore these interactions using a suite of molecular and multi-omic analytical techniques to answer core questions about PyC activity in humans. 1) This project will reveal mechanisms of transport of PyC and PyC-metal complexes by absorbing and excretory epithelia using labeled PyC standards. 2) It will explore PyCs as a dietary means of modifying nutrient metal absorption and distribution in in vivo experiments involving mineral-deficient mouse models. Complementary studies will investigate PyCs as a dietary means to promote heavy metal excretion using both in vitro and in vivo models. 3) Finally, methods for reliable detection of PyC and PyC-metal complexes in human samples, using established analytical methods from the plant sciences and PyC-biased re-extraction of preexisting human metabolomics data, will be explored and optimized. Successful completion of this project will lay the foundation for a new topic of study within metal homeostasis research. A fundamental understanding of PyC and PyC-metal uptake, distribution and excretion will be established, and key methodology for subsequent clinical translational research on PyCs as dietary modifiers of metal homeostasis will be provided. More widely, this project will highlight small molecule actors in regulation of metal availability and distribution that have thus far gone unnoticed and may be key to any number of future developments in metal homeostasis research.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY While HER2+ breast cancers (BCs) can be therapeutically targeted via HER2-targeted agents, response depends on HER2 status; tumors with residual HER2 expression (HER2-low) do not respond. HER2-low status have been described in triple negative (TNBC) and HR+ BCs, and includes primary tumors, metastases, and circulating tumor cells (CTCs). Recently, patient benefit has expanded to HER2-low tumors with the development of HER2-targeted antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd), which suggest that the presence of a small reservoir of HER2+ cells is therapeutically actionable. This is of upmost importance, considering an estimated 50% of all diagnosed BCs are actually HER2-low. CTCs isolated and cultured from HER2-, metastatic HR+ and TNBC patients can divide to produce HER2+ cells with as few as 3 population doublings, without the acquisition of genomic alterations that activate HER2. Similar results were obtained from HER2+ CTCs, which can yield HER2- daughter cells with similar division kinetics. These results demonstrate HER2 expression is plastic and suggest that HER2- and HER2-low BCs may respond to T-DXd at least in part because of the maintenance of a heterogeneous HER2 state. Thus, designing treatment strategies to maximize therapeutic benefit to T-DXd in the HER2-/low patient population remains an unmet clinical need. We and others have found HER2 plasticity in cell culture models and CTCs derived from HER2- BC. We recently observed that ionizing radiation (IR) increases HER2 expression and HER2 heterogeneity in HER2- BC models. We also find that IR increases cell death when paired when T-DXd in models of HER2- BC. Taken together, we hypothesize that IR sensitizes models of HER2- and HER2-low BC to the HER2- targeted ADC T-DXd. To test this hypothesis, we will employ established cell culture and CTC models of heterogeneous HER2- and HER2-low BCs. We will first determine the extent to which IR sensitizes these models to T-DXd. Transcriptomics post-IR will provide insight into how IR remodels gene expression to support HER2 plasticity. Using these in vitro models, we will test whether IR sensitizes BCs to T-DXd. These studies will inform which patient populations may benefit from combined IR and T-DXd based on HER2 expression. We will then pivot and investigate whether IR sensitizes in vivo models of HER2-/low BC to T-DXd, by examining whether IR coupled with T-DXd reduces tumorigenesis and extends survival. Correlative studies will be performed to examine the duration of elevated intratumoral HER2 expression and heterogeneity to define the optimal time window for IR prior to T-DXd. We will then examine whether IR can resensitize T-DXd-resistant tumor models to T-DXd. These studies will provide insight into the timelines and context(s) that IR can be used to stimulate a therapeutic response to T-DXd, which could be leveraged for future investigator-initiated clinical trials.

NIH Research Projects · FY 2026 · 2026-04

Project Summary The majority of Americans will experience a traumatic event during their lifetimes, but only a subset experience chronic negative psychiatric outcomes such as post-traumatic stress disorder (PTSD) and depression. Several cohort studies over the past 10 years have identified brain-based risk mechanisms early after trauma, which predict risk for chronic symptoms such as hyper-arousal, intrusive memories of the trauma, and negative affect. One of the most widely-replicated and theoretically-grounded such mechanisms involves early high amygdala responses to threat cues. Given the strength of current evidence, we propose that this is an actionable target for intervention early post-trauma, to prevent chronic impairing and distressing symptoms. Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that can induce functional brain changes as potential intervention for neuropsychiatric disorders. Emerging findings along with our preliminary data suggest that the amygdala can be reached and dampened via stimulation of a functionally connected cortical prefrontal area. Here we propose that using TMS to dampen amygdala hyperreactivity will prevent a cascade of symptoms that could develop following trauma exposure. We propose to identify Emergency Department patients who have experienced a recent traumatic event (meets DSM-5 Criterion A), and who have high initial PTSD symptoms at 1 week post-trauma. In the R61 phase we will deliver a staged single-blind TMS intervention with a lead-in sham, followed by active treatments with increasing doses, measuring amygdala reactivity at each phase. R61 milestones involve: 1: Target engagement: Determination that active TMS versus sham decreases within-subject amygdala threat reactivity (decrease in reactivity to fearful faces). 2: Dose response: Determination that 4 vs 1 session of TMS decreases these same targets. 3: Safety and feasibility: Demonstrating feasibility of recruitment and retention (75% of participants are able to complete 75% of sessions), and no Serious Adverse Events (SAE) deemed related to the TMS intervention. If these are met, the R33 phase will involve a randomized double-blind sham-controlled trial, providing a double- blind replication of the immediate effects on the amygdala target and 1-month later, as well as longitudinal assessments of TMS effects on both PTSD and depression symptoms over 3 months post-trauma. The research environment at Emory University School of Medicine will provide excellent support for the successful completion of the proposed research, particularly with state-of-the-art neuroimaging facilities, a well-developed infrastructure for identifying participants at risk for chronic trauma-related symptoms through the Grady Trauma Project and Grady Healthcare System, and a strong community of experts in trauma and neuromodulation. If the hypotheses are confirmed, this study will lay the groundwork for future early intervention trials using non- invasive dampening of amygdala reactivity to prevent chronic trauma-related symptoms.

NIH Research Projects · FY 2026 · 2026-04

PROJECT ABSTRACT Substance use via injection carries very high risk for overdose, HIV, and hepatitis C virus (HCV) infection. Injection drug use (IDU) is highly stigmatized and criminalized in the U.S., making health information difficult to collect from people who inject drugs (PWID). PWID population size estimates (PSEs) are needed for use as denominators of PWID health indicators (e.g., number of PWID with an HIV infection), allowing these health indicators to be expressed and compared as a function of the size of at-risk populations. However, the most recent standardized, local PWID PSEs reflect 2007, an early stage of the dynamic opioid crisis in the U.S. Without current local PWID PSEs, the extent to which changes in overdose deaths and infectious diseases reflect changes in PWID population size, versus differences in substances or behaviors, is unknown. This is important because there are specific public health interventions that aim to prevent transitions to injection drug use versus reduce risk for adverse outcomes among current PWID. Updated local PWID PSEs are critically needed to enable policy makers and public health practitioners to advocate for resources to improve PWID health. These data can facilitate allocation of resources, effective implementation of interventions, and monitoring for change in PWID health outcomes over time. Among PWID, rates and risk factors for overdose and infectious diseases vary substantially by age, therefore different interventions are needed based on age distributions of populations. In addition to population size, it is important for local jurisdictions to understand the age structure of their PWID populations, so that they may deliver age-tailored responses. In collaboration with 11 city health departments, we propose to extend and improve our team’s hybrid estimator model for creating a national PWID PSE to create overall and age-specific PWID PSEs in 11 large cities. Aim 1: To develop novel methods for estimating PWID population size in 11 U.S. cities, overall and by age. Aim 1a: To measure PWID risk for overdose death (e.g., ratios of non-fatal to fatal overdose and medically attended to unattended overdose) and infectious diseases (syringe coverage, HIV and HCV diagnosis rates). Aim 2: To predict the prevalence of PWID at unmeasured locations within cities, using Bayesian INLA-SPDE methods and demographic and place-based risk factors, and to map predicted PWID population density alongside locations of services. Aim 3: To disseminate findings using AIDSVu and HepVu platforms, which will also host a novel resource sharing center for estimating PWID population size. We anticipate that making PWID PSEs and infectious disease indicators widely available, together with a resource sharing center for computing local estimates, will incite interest in other jurisdictions for creating PWID PSEs. This work is a critical step forward from our published national PWID PSE methodology to standardized sub-national estimates, illuminating where resources are most needed to promote PWID health.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Transplantation serves as an effective remedy for end-stage organ failure. Standard-of-care treatment with calcineurin inhibitors (CNI) have successfully reduced immune-mediated allograft rejection, at the cost of damaging the allograft over time (i.e., nephrotoxicity). Belatacept (CTLA-4Ig variant) is associated with improved kidney function in renal transplant recipients. However, use of CTLA-4Ig was associated with increased rates of early acute rejection compared to CNI. CD8+ memory T cells are generally less reliant on costimulatory signaling for their activation and mount a more rapid and robust response. Therefore, the recipients’ immunological memory may be a potential mediator of acute rejection. Several groups have identified subsets of memory T cells underlying belatacept-resistant rejection. We interrogated the phenotypes of these human memory T cells and identified the shared expression of a coinhibitory molecule T cell immunoreceptor with immunoglobulin domains (TIGIT), thus presenting TIGIT as a direct target on CD8+ memory T cell subsets. Numerous groups have used immunomodulatory agents as therapeutics for a range of pathologies (i.e., transplant, cancer, autoimmunity). As an example, the blockade of TIGIT and PD-1/L1 has shown promising results for the treatment of cancer. Here, we investigate the ability of TIGIT agonism to minimize allograft rejection mediated by the recipient’s immunological memory. Our preliminary data show that TIGIT agonism plus CTLA-4Ig improves allograft survival in a murine skin graft model of naïve and memory CD8+ T cells. The addition of TIGIT agonism is accompanied with a reduction in the numbers of CD8+ memory T cells in the allograft of both models. These data highlight the ability of TIGIT agonism to target CD8+ memory T cells either directly or indirectly by Tregs to improve allograft survival. We aim to further evaluate the mechanisms underlying the survival benefit employed by TIGIT agonism using murine skin graft models. We believe TIGIT agonism may hold promise as an adjunct immunotherapy to attenuate CD8+ memory T cell mediated costimulation-blockade resistant rejection. With reduced immunosuppression induced toxicities and reduced rates of acute rejection, quality of life for transplantation patients would be increased alongside a reduced need for re-transplants.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT: Suboptimal gestational weight gain (GWG) is a modifiable risk factor for adverse pregnancy outcomes, postpartum weight retention and obesity, and subsequently, the long-term development of non-communicable diseases (NCD) among women and children. In South Africa, 45% of women exceed the Institute of Medicine’s (IOM) recommended weight gain in pregnancy, and 38% gain too little weight, putting them at risk for poor perinatal and postpartum NCD outcomes. Women in low- and middle-income countries (LMICs) with a high burden of HIV and NCDs, such as South Africa, are at particularly high risk of suboptimal weight gain due to poor diet quality, limited physical activity, high levels of psychosocial stressors, and, for women with HIV (WHIV), possible antiretroviral-associated weight gain. By supporting healthy GWG, there is strong potential to reduce postpartum NCD risk and improve perinatal outcomes for women with and without HIV. However, few GWG interventions are available for delivery in LMICs, and none have been adapted to address excessive and inadequate GWG or enhanced to meet the unique needs of women with and without HIV. To address this gap, our team previously developed an innovative, theoretically driven group prenatal care (GPNC) intervention and adapted it to reduce GWG and NCD (GPNC-NCD) risk in resource-constrained settings. GPNC-NCD is an evidence-based intervention, based on social cognitive theory, that builds health literacy, self-efficacy, social support, and satisfaction with care, leading to improved perinatal, GWG, NCD, and perinatal outcomes. The goal of this proposal is to adapt the GPNC-NCD intervention for use in South Africa to support healthy GWG (not too much or too little), enhance it to address the needs of WHIV and without HIV, and evaluate the feasibility, acceptability, and preliminary efficacy of the intervention to improve GWG, NCD, perinatal, and HIV care and prevention outcomes in a pilot randomized trial. Our specific aims are: 1) to adapt the GPNC-NCD intervention for use in South Africa to support healthy GWG and enhance it to address HIV status as a driver of GWG, and 2) to determine the feasibility, acceptability, and preliminary efficacy of the adapted and enhanced GPNC intervention. In a pilot trial, 80 women will be individually randomized by HIV status at ≤14 weeks gestation to GPNC (n=20 WHIV, n=20 HIV-) versus usual care (n=20 WHIV, n=20 HIV-). We hypothesize that adapted GPNC will be feasible, acceptable and show preliminary efficacy to improve GWG, NCD (blood pressure, breastfeeding, diet, physical activity), HIV care/prevention (ART adherence, viral suppression, or PreP uptake), and perinatal (birthweight, large-for-gestational age, cesarean delivery) outcomes. This proposal addresses the goals of PAR-23-191 by leveraging the evidence-based GPNC intervention to support healthy GWG, addresses HIV-NCD disparities, and builds capacity for HIV/NCD research in LMICs. If successful, our adapted GPNC intervention has strong potential to serve as a model for how to integrate NCD and HIV care and prevention support into routine prenatal care in LMICs to improve perinatal, HIV, and NCD outcomes.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY In kidney, type B and Non-A, non-B intercalated cells (ICs) secrete HCO3- and absorb Cl- through apical pendrin-mediated Cl-/HCO3- exchange, which helps correct metabolic alkalosis and maintain intravascular volume. While this mechanism was likely critical to primitive man’s survival, we hypothesize that it augments the hypertensive response of modern man to common hypertensive stimuli such as a high-salt diet and conditions of high angiotensin II (ang II). This proposal identified a novel pathway that may explain how ang II upregulates pendrin. Our data suggest that pendrin’s ang II response depends on immune cell activation and consequent cytokine release, revising the widely held view that ang II stimulates pendrin solely through a direct angiotensin 1a receptor (AT1a)-mediated signaling in pendrin-positive ICs. Inhibiting lymphocyte activation or eliminating T lymphocytes and other innate lymphoid cells blunts the ang II-induced increase in apical pendrin abundance. Moreover, pendrin abundance increases with the application of cytokines that are released in response to ang II, whereas pendrin abundance falls when these cytokines are reduced. Our data also show that ang II upregulates pendrin abundance and activity largely through reactive oxygen species (ROS), which we hypothesize occurs through pendrin cysteine oxidation and through the production of isolevuglandins (IsoLGs), which are neoantigens that enhance the immune response. We therefore propose that Ang II acts both through immune cell cytokine release and acts directly on the IC AT1a receptor to upregulate pendrin. We also propose that ang II upregulates pendrin through IsoLGs and through ROS- induced pendrin cysteine oxidation. Our data point to a new feed-forward amplifying loop whereby ang II- induced ROS and IsoLGs upregulate pendrin, which raises blood pressure and therefore increases ROS and IsoLGs further. We also hypothesize that pendrin impacts renal ROS and IsoLGs through blood pressure changes primarily via its action in the kidney. This proposal examines the ang II signaling cascade that regulates pendrin and will define pendrin’s role in blood pressure regulation and inflammation. Aim 1 will determine if ang II upregulates pendrin by stimulating cytokine release by immune cells and/or through a direct effect on the IC AT1a receptor. Aim 2 will determine if ang II increases apical membrane pendrin abundance through IsoLGs and through pendrin cysteine oxidation by reactive oxygen species. This aim will also determine if pendrin augments the ang II pressor response just through its action in kidney. To accomplish these objectives, we will examine ROS and IsoLG as well as pendrin abundance and function in ang II-treated mice as a model of human hypertension and in cell models. Pendrin abundance, subcellular distribution and function will be determined with immunoblots, immunofluorescence, immunohistochemistry, and immunogold cytochemistry. Relevance: This proposal examines the pathogenesis of hypertension.