Yale University

NIH Research Projects · FY 2026 · 2026-05

Project Summary The goal of this project is to understand how prior knowledge shapes new learning. Research has shown that the congruency between new information and existing schemas can facilitate new associative learning. For example, people are better at remembering the association between a specific object and a specific scene when their categories are semantically related. Although this effect is well-documented behaviorally and linked to certain brain systems, the precise mechanisms by which schema congruency enhances hippocampal and cortical processing during visual associative learning are unknown. Here we explore the fine-grained neural dynamics involved in schema-based learning. We test a prominent mechanistic theory — the representational coherence hypothesis — which proposes that schema congruency benefits associative learning by causing stimuli to have more stable and resonant neural representations. We test this theory with two varieties of magnetoencephalography (MEG), one an established method (SQUID) and the other a next-generation technology (OPM), both of which provide a more time-resolved characterization of object and scene processing than fMRI and better separation and localization of signals to brain regions than EEG. Participants undergoing SQUID (Study 1) or OPM (Study 2) MEG will associate pairs of natural objects and scenes. The object in each pair will be either schema-congruent (SC) or schema-incongruent (SI) with the scene category. Subsequent memory recall for the scene associated with each object will be probed after a 10- minute delay. Pattern classifiers will be trained to decode scene and object categories in a separate localizer task, then applied to the encoding and retrieval trials of SC and SI pairs. We will compare the temporal evolution of classifier evidence for the scene and object in SC and SI pairs and examine the phase coherence of these timeseries, the alignment of the classifier outputs with source-localized hippocampal theta phases, and the interaction between medial prefrontal cortex and hippocampus. This project will yield critical new insights into why some information is easy to learn and how this learning is supported by brain dynamics and systems.

NIH Research Projects · FY 2026 · 2026-05

Therapeutic Rewiring of Colorectal Cancer BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death and increasingly affects young adults. Our team has recently made paradigm-shifting discoveries in CRC oncology, biology and signalling, while also establishing proof-of-concept for therapeutic reprogramming and hyperactivation-induced lethality, pioneered the development of the first direct oncogene activator and novel receptor-targeting strategies, with extensive expertise in translating basic research into drug development. Our proposal now unites two key concepts under a single cancer rewiring project: 1) Hyperactivation — Emerging data suggest that many cancer cells are susceptible not only to inhibition of oncogenic signaling - but also overactivation of these same pathways. In CRC the three major signaling pathways that are dysregulated (WNT, MAPK and PI3K) all show evidence for this ‘Goldilocks’ (‘just right’) phenomenon. Moreover, emerging preclinical candidate therapeutics are poised to, for the first time, exploit these newfound vulnerabilities. 2) Cell-state Rewiring — CRC is also notable for the diverse sets of cell-states that drastically modulate the response to clinical therapeutics and likely will influence both response to chemotherapy, targeted pathway inhibition and pathway activators. We are similarly poised to rewire these states to enhance the response to existing and emerging therapies. AIM: Develop clinically tractable strategies using signalling activators and inhibitors to destroy cancer cells via hyperactivation and rewire cancer cells towards vulnerable cell-states. APPROACH: REWIRE-CAN (Reprogramming Epithelial WIRing to Eradicate CANcer) will address this Cancer Grand Challenge by: - DISCOVERING novel agents to modulate and hyperactivate oncogenic pathways (WP1) - DEVELOPING approaches to use novel signalling activators to treat cancer via signalling hyperactivation and cell-state rewiring (WP2) - TRANSLATING therapeutic rewiring strategies into preclinical and clinical proof-of-concept studies (WP3) METHODS: REWIRE-CAN will combine functional analysis of patient samples with advanced drug discovery, including functional genetic screens, clinical bio-specimens, patient-derived organoids, animal models, and custom single-cell signalling technologies. This integrated approach will define combinatorial signalling dependencies in human CRC and allow us to directly translate these findings into in vivo therapeutic studies prior to clinical application. IMPACT: REWIRE-CAN will harness novel signal activators and the unique signalling biology of CRC to create a roadmap for sensitising cancer cells to therapy through signalling rewiring. Our lasting impact will be to identify novel therapeutics for advanced CRC, supported by in vivo proof-of-concept and tractability towards clinical candidate development. REWIRE-CAN will develop much-needed new therapies for CRC and also act as an exemplar for emerging signalling activator therapy in cancer.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT B cells are a key component of adaptive immune responses, and their differentiation from naive to long-lived antibody-secreting plasma cells provides us with protection from recurrent infections. Understanding the regulatory logic underlying B cell fate decisions, for example, the differentiation choices generating memory or plasma cells, offers the possibility of improved vaccination or immunotherapy strategies. Although B cell differentiation in humans cannot be directly observed, several computational methods have been proposed to infer regulatory networks from single cell transcriptomic data. However, existing transcriptional trajectory analysis approaches assume that the data contain cells representing a sufficient number of states along a continuum of dynamic changes. Applying such methods to B cell fate decisions is problematic since adaptive immune responses are spatially distributed, with cells migrating across many tissues (eg, lymph nodes, blood, and bone marrow), and are sampled at discrete time points often spanning days or weeks. Recent advances in high-throughput sequencing now allow for the simultaneous determination of the B cell antibody receptor (BCR) along with the cellular transcriptional profile at single cell resolution. The high variability of the BCR provides a “fingerprint” that can be used to identify the transcriptionally distinct descendants of each naive B cell (a “clone”). Further resolution of ancestor-descendant relationships can be accomplished through reconstruction of phylogenetic lineage trees based on somatic hypermutation patterns (mainly point mutations that accumulate through an enzymatically-driven process during adaptive immune responses). I propose to integrate B cell lineage trees with transcriptional trajectory analysis to resolve B cell differentiation processes across space and time. I will also improve methods for identification of clonally-related B cells by explicitly modeling B cell phylogenetic relationships as part of clonal analysis. Working closely with experimental collaborators, I will apply these methods to longitudinal human immune profiling data from multiple tissues. This will serve as method validation and may also provide knowledge that will lead to designing more effective vaccines or immunotherapies. These are early but critical steps in my long-term goal of connecting B cell migration and differentiation patterns to strategies for vaccination and other therapies.

NIH Research Projects · FY 2026 · 2026-04

Alzheimer’s disease (AD) is a devastating condition without effective treatment. Novel approaches to improving treatment are greatly needed. Accumulating evidence suggests tau as a viable target for AD therapy. Recent preclinical studies have shown promise in tau-targeting molecular therapy through suppression of the tau-coding gene MAPT using antisense oligonucleotides (ASOs). These findings have led to clinical tests, showing tau reduction therapy to be generally safe and well-tolerated. However, ASO-based therapy is transient, requiring frequent administration for long-term efficacy. Conversely, CRISPR-based genome editing technology can induce genetic knockouts at the genomic level, offering persistent therapeutic benefits. The most significant hurdle for clinical translation of genome editing therapies has been the lack of safe and efficient delivery methods for the CRISPR machinery to the brain. In this application, we aim to leverage our recent success in development of stimuli-responsive traceless engineering platform ribonucleoproteins (STEP RNPs) for delivery of CRISPR-based genome editing to the brain to demonstrate the potential of tau-targeted genome editing therapy for treatment of AD. In preliminary work, we showed that a single intrathecal administration of genome editing therapy via cRNP, a lead STEP RNP, enabled brain-wide editing of neuronal cells and achieved long-term therapeutic effects for neurodevelopmental diseases. Building on this progress, we propose to optimize STEP RNPs for delivery of genome editing to neuronal cells for tau reduction in Aim 1, to characterize MAPT-targeting genome editing therapy for AD treatment in mouse models in Aim 2 and to preliminarily characterize RNP delivery and tau reduction in nonhuman primates (NHPs) in Aim 3. Successful completion of this application could result in a long-lasting therapy for effective AD management through a single administration and provide a non-viral system for safe and efficient delivery of genome editing to the brain, adaptable for targeting other AD-causing or associated genes.

NIH Research Projects · FY 2026 · 2026-04

Project Summary The Peru Amazon region of Loreto (capital, Iquitos) accounts for 95% of all malaria in Peru, and ranks as contributing to ~25% of all malaria cases in the Americas. Peru has repeatedly launched elimination plans, most recently in 2022, based on case-finding strategies, field-deployable molecular diagnosis, and vector control measures conceived within the previously funded, NIAID-supported, Amazonian ICEMR network. Two contexts remain a challenge to achieve malaria elimination goals: (i) residual malaria transmission with sustained hypoendemicity despite the use of currently available interventions, and (ii) focal hyperendemic transmission in hard-to-reach Indigenous populations. This proposal focuses on residual urban and close-by and remote riverine transmission areas with increasing proportions of asymptomatic cases, regardless of age. Malaria transmission in these remote areas remains high and difficult to control, and the past two years have seen important rises in malaria cases. We first aim to characterize a wide range of sociodemographic, behavioral, and environmental factors that, in addition to human genetics, contribute to individual risk of malaria (re)infection and disease in the Amazon. We will estimate the relative contribution of genetic and nongenetic (potentially modifiable) factors to individual malaria risk variation and identify risk profiles in populations from residual malaria settings in Peru. Next, we will apply network analysis to analyze the interconnectedness of malaria parasite carriers between remote and more proximal sites, which we hypothesize leads to continued malaria transmission with residual malaria settings as an important source. In addition, we will track malaria transmission trends and identify hotspots in remote indigenous populations in Peru by applying field-deployable molecular diagnosis and modeling sequential antibody measurements. In summary, we will advance knowledge on individual malaria risk profiles and the impact of targeted interventions in residual malaria contexts. We will also characterize malaria transmission in hard-to-reach areas where the malaria burden is poorly understood and mitigated. Collectively, this study will make significant contributions by integrating and translating diverse data and analytic frameworks into actionable knowledge and evidence to support tailored malaria elimination efforts in Peru, elsewhere in South America, and similar contexts in the world beyond, including the protection of United States domestic and military interests.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Sepsis is a syndrome of physiologic dysregulation and multiorgan dysfunction resulting from infection. According to the World Health Organization, sepsis has an annual global incidence of 50 million and mortality rate of 20-40% - accounting for 20% of global deaths. The Agency for Healthcare Research and Quality estimates that sepsis accounts for over $50 billion in U.S. annual healthcare expenditures (2024). Thus, there is a tremendous need for improved treatment approaches for sepsis. Dr. Eric I. Elliott’s research in the Wang lab using human samples and mouse models has revealed that: (1) adaptive regulation of carnitine metabolism in bacterial and viral sepsis promotes survival; (2) following priming by bacterial inflammation, L-carnitine activates the Pyrin inflammasome; and (3) the high-affinity L-carnitine transporter SLC22A5 is a potential target to modulate inflammation and survival. Employing the novel SLC22A5 conditional knockout mouse developed by Dr. Elliott, this proposal seeks to understand tissue-specific roles of carnitine metabolism in sepsis in order to: (1) determine how carnitine metabolic reprogramming impacts survival, (2) assess the therapeutic role of cell-specific SLC22A5-targeting, and (3) identify additional pathways and molecules that could be targeted to improve sepsis outcomes. Furthermore, as metabolomic and GWAS studies implicate L-carnitine, SLC22A5, and Pyrin in many other inflammatory diseases, the pathways and targets elucidated in this proposal may have translational relevance extending beyond sepsis. This proposal outlines a rigorous five-year training program for Dr. Eric I. Elliott, MD, PhD, to prepare him for his independent research career. The principal investigator, Dr. Elliott, is a physician-scientist who completed his MD/PhD training at the University of Iowa where he studied the regulation of inflammasome activation by mitochondrial cardiolipin. He completed his internal medicine residency and infectious disease fellowship in the Yale Physician-Scientist Training Program, and is currently an Instructor in the Section of Infectious Diseases at Yale. He joined the laboratory of Dr. Andrew Wang, MD, PhD, to study the metabolic adaptations in sepsis. Dr. Wang is an experienced mentor and expert in neuro-endocrine-immune interactions in homeostasis, stress, and inflammation. This proposal will provide Dr. Elliott with additional scientific and technical expertise in assessing mitochondrial metabolism, microscopy, RNA sequencing, and translational genetics research pertinent to the planned research and its future applications. Furthermore, Dr. Elliott will receive training in scientific communication, writing, and laboratory management. He will complete his research and training objectives with the tremendous support and resources provided by the Yale Department of Internal Medicine (Section of Infectious Diseases), the mentorship of Dr. Andrew Wang, and the guidance of his strategically assembled advisory committee. Successful completion of the proposed research and training will ensure Dr. Elliott attains his goal of becoming a leader in the field of inflammation-induced metabolic reprogramming.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract There are 100+ serotypes of pneumococcus, and currently available pneumococcal conjugate vaccines (PCVs) protect against up to 20 of these serotypes. However, despite the use of PCVs for more than 20 years, there is still a considerable burden of pneumococcal disease in the United States. While PCVs have driven down the burden of many vaccine-targeted serotypes, other serotypes have emerged, and certain vaccine- targeted serotypes have re-emerged in recent years. The drivers of these dynamics, especially the re- emergence of vaccine-targeted serotypes, are not well-understood. The next several years will bring tremendous change to the pneumococcal vaccine field, with several next-generation PCVs that target up to 31 serotypes undergoing late-stage clinical development. These new PCVs cover additional serotypes but often have lower immunogenicity against the targeted serotypes. Understanding the drivers of serotype dynamics is essential to make informed decisions about which of the pneumococcal vaccines should be used in different age groups and populations. The proposed work will provide novel insights into the mechanisms driving serotype re-emergence and differences in impact between vaccines. We will use mathematical and statistical models to test specific hypotheses about the drivers of these patterns and will then evaluate real-world serotype patterns using newly collected colonization data linked with vaccination history. These insights will inform models of serotype dynamics that will be used to evaluate the potential impact of different strategies using currently available PCVs as well as new PCVs that are likely to become available in the next few years. This study is innovative in providing a novel understanding of the dynamics of pneumococcus and the tradeoffs of policies that would incorporate new PCVs. We will do this with an innovative mix of primary data on colonization and secondary data sources, combined with statistical and mathematical transmission models. The outcomes from this work will provide important insights that can be used by vaccine developers, healthcare providers, and policy-makers to inform how to optimally design and deploy new PCVs over the next several years.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Follicular B cells have two developmental pathway options upon activation: the canonical germinal center pathway and the extrafollicular pathway. The germinal center is a key microanatomical structure in which B cells undergo stringent selection and mutation, resulting in a pool of B cells with high-affinity for the initiating foreign antigen and little to no autoreactive B cell clones. On the other hand, B cells that enter the extrafollicular pathway do not undergo stringent selection and therefore can result in not only the activation of foreign antigen-specific B cells but also self-reactive B cell clones. It has been demonstrated, by our lab and others, that a unique type of extrafollicular B cell has the capacity to produce both protective and pathogenic antibodies. This B cell compartment, composed of B cells that co-express Tbet and CD11c, plays a key role in the protection against many bloodborne pathogens but also has been implicated in the progression of autoimmune diseases. While antibodies from Tbet+CD11c+ B cells are mutated, these cells, in the context of acute infection, do not enter the germinal center reaction. It is unknown whether or not Tbet+CD11c+ B cells have the capacity to enter the germinal center during differing inflammatory environments, and whether the Tbet+CD11c+ B cell compartment is comprised of two independent pools, one with protective functions or one with pathogenic functions, or if the compartment is comprised of polyreactive Tbet+CD11c+ B cells. We hypothesize that Tbet+CD11c+ B cells have germline BCR sequences that allow for the recognition for both viral and self-antigen and that, due to a decrease in selection pressure experienced by extrafollicular B cells, Tbet+CD11c+ B cells that recognize both types of antigens are able to expand and participate in the immune response regardless of the initiating stimulus and inflammatory environment. My first aim is to uncover the basis for Tbet+CD11c+ autoreactivity during acute viral infection. To determine this, I will sequence viral antigen-specific Tbet+CD11c+ B cells, reexpress their immunoglobulin (Ig) sequences, and test their reactivity to self-antigen. I will also revert their sequences back to germline, reexpress the germline Ig sequences, and determine if the autoreactivity is retained. My second aim is to uncover how the autoreactive B cell pool differs under unique inflammatory environments. To this end, I will determine the contribution of Tbet+CD11c+ B cells to the autoreactive pool during chronic viral infection and chronic inflammation in the absence of virus using flow cytometry, determining antibody specificities, and investigating if Tbet+CD11c+ B cells contribute to the germinal center reaction during chronic inflammation using transgenic mice models and single-cell B cell receptor signaling. If successful, my project will uncover a key relationship between protective and pathogenic B cells. Moreover, my project will help elucidate how the behavior of extrafollicular B cells is influenced by its surround environment.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Osimertinib (osi), a third-generation EGFR tyrosine kinase inhibitor (TKI), has significantly improved outcomes for patients with EGFR-mutant lung cancer, but resistance is inevitable, and it is not curative. Understanding the mechanisms driving resistance is critical to developing more effective treatments. Emerging evidence suggests that osi induces replication stress. I am investigating ATR, a kinase activated by replication stress, for its role in promoting cell cycle progression after osi treatment. Additionally, osi-induced replication stress may sensitize tumors to DNA-damaging chemotherapy by overwhelming DNA repair machinery. Consistently, recent clinical trials have shown that combining osi with chemotherapy improves progression-free survival, and trastuzumab deruxtecan (TDXd), the only antibody-drug conjugate approved in lung cancer, is effective against EGFR-TKI- resistant tumors. The central hypothesis of this study is that osi-induced replication stress activates ATR to attenuate this stress and promote cell cycle progression, leading to resistance. Furthermore, ATR inhibition and TDXd is expected to delay tumor relapse following osi treatment. Using patient-derived models, this project will: Aim 1) determine if ATR is necessary to promote cell cycle progression during the acquisition of osi resistance and identify ATR-dependent pathways mediating this process. Aim 2) will evaluate if residual tumors persisting after osi treatment exhibit elevated replication stress and ATR activity, and whether ATR inhibition and TDXd can delay relapse. Human tumors treated with EGFR-TKIs, +/- chemotherapy, will also be profiled using imaging mass spectrometry (IMC) to detect if DNA damage repair (DDR) activity correlates with treatment response and predict sensitivity to ATR inhibition and TDXd. This research will address the critical need to understand the role of ATR activity in osi resistance and provide novel insights into the presence of DDR in human tumors. Together these insights will explore the clinical potential of ATR inhibitors and TDXd for treating EGFR-mutant tumors. The project will utilize Yale School of Medicine’s (YSM) state-of-the-art facilities, confocal microscopes from the Yale Center for Cellular and Molecular Imaging (CCMI) and a Cytometry Time-Of-Flight (CyTOF) Helios Imaging Mass Cytometer for the IMC study. Access to patient-derived cell lines (PDCs) and xenograft tissues (PDXs) from the Yale Advanced-Stage Lung Cancer Tissue Collection Study, managed by the Sponsor, will further facilitate this research. This F31 Fellowship will provide the Principal Investigator (PI) with essential training in advanced techniques such as mass spectrometry and IMC while supporting the PI's development in translational research skills and scientific communication. Additionally, acquiring this training is crucial for the PI who intends to pursue a future career studying therapeutic biomarkers, that target synthetic lethal interactions, to bridge gaps in cancer patient care with translational research. Leveraging the F31 Fellowship to maximize resources and training will ensure the project's success and support the PI’s growth into an independent researcher.

NIH Research Projects · FY 2026 · 2026-04

Project Summary PD-1 pathway targeting antibodies have improved patient outcomes in lung adenocarcinoma (LUAD). Unfortunately, most LUAD patients do not yet benefit from these therapies, and it is not clear why. Robust responses to PD-1/PD-L1 blockade require that the intratumoral CD8 T cells are in a progenitor-exhausted (TPEX) state, as TPEX cells proliferate and give rise to cytotoxic effector CD8 T cells (TEFFs). Yet, we and others have found that tumor-specific TPEX cells are primarily housed in the tumor-draining lymph node (tdLN) associated with the lung. Via migration, these cells continually replenish the tumor migration, underscoring the critical role of the tdLN as a reservoir of stem-like CD8 T cells. However, because the tdLN is the site of long- term maintenance, we hypothesize that the biology of tumor-specific TPEX and their differentiated progeny is shaped by the interactions and signals they receive in this site. Here, we propose in-depth studies on the mechanisms controlling the differentiation and maintenance of TPEX populations in the tdLN. Our proposal integrates genetically engineered LUAD models, CRISPR-based perturbations, and single-cell approaches to dissect this process. Specifically: 1. We will define how KLF2 and T-bet prevent exhaustion by repressing exhaustion-related genes (e.g., TOX) and implementing cytotoxic effector programs as T cells differentiate across the tdLN and tumor. 2. We will determine how IL-21–BATF signaling impacts on TPEX → effector CD8 T cell transitions, and the role of KLF2 in this process. We previously showed IL-21 is provided by T-follicular helper CD4 T cells in the tdLN, and we will leverage models with and without TFH responses to pinpoint how IL-21 signaling promotes CD8 T cell cytotoxicity and limits exhaustion. 3. KLF2 is transiently downregulated by TCR signals. We will determine if KLF2 downregulation is necessary for differentiation in the tdLN and the role that TCR-dependent signals play in maintaining T cell stemness in the tdLN. Our studies will investigate immune signaling pathways and transcriptional networks regulating CD8 T cells in the tdLN, elucidate mechanisms for the provision of IL-21 and its role in driving effector function, and explore the interplay between TCR and KLF2 in shaping CD8 T cell fate. These insights will shed light on immunoregulatory mechanisms that determine whether tumor-specific CD8 T cells maintain anti-tumor functions or become dysfunctional. By illuminating the biology of the tumor-specific TPEX cells in the tdLN reservoir, our goal is to identify entry points for mobilization or reprogramming through targeted interventions, to boost the efficacy of therapies against LUAD.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Human gene data has fundamentally transformed our understanding of human disease. However, a major barrier for leveraging genomic data lies in the fact that many immune conditions, in particular autoimmune disease, often show complex etiologies. Many candidate risk genes show low explained heritability, complicating discovery of pathogenic mechanisms. Identification of monogene defects that strongly contribute to disease pathologies carries broad relevance for understanding the complex basis of autoimmunity. We have discovered novel loss-of-function (LOF) gene defect in a gene called ZFYVE21. ZFYVE21 is an ancient endosome-associated protein that shows increased expression in cells showing high endo- phagocytic activity like macrophages (MΦ). We previously identified ZFYVE21 as an essential mediator of NF- κB. Affected individuals with LOF of ZFYVE21 developed mucosal pathologies including ulcerative colitis (UC), a form of inflammatory bowel disease (IBD), and patient PBMCs showed signs of immune dysregulation including overexuberant innate signaling and impaired bacterial killing. We call this uncharacterized condition, ZFYVE21-Associated Disorder (ZAD). In preliminary studies, we explored how LOF of ZFYVE21 dysregulates innate immunity. Via a team approach, we collaborated with an IBD specialist, immune geneticist, structural biologist, and microbiologist. We harmonized in silico, in vitro, and in vivo approaches, and we generated 2 new mouse models including conditional loss of ZFYVE21 and mice systemically reconstituted with ZFYVE21 gene variants. Using our team approach, we preliminarily found that LOF of ZFYVE21 led to a MΦ intrinsic defect causing exacerbated colitis in vivo. These studies informed a new hypothesis that LOF of ZFYVE21 promotes MΦ dysfunction. Pathogen control processes including innate signaling and bacterial killing are essential for intestinal homeostasis. In 2 non-overlapping Specific Aims, we explore these processes as a basis for explaining immune dysregulation and development of mucosal immune pathologies with LOF of ZFYVE21. In Aim 1, we will explore how mutant ZFYVE21 proteoforms affects innate signaling, and in Aim 2 we will define how loss of ZFYVE21 protein stability impairs bacterial killing. We identified ZFYVE21 as a novel immune regulator in humans. Gene defects in ZFYVE21 have not been described for any human immune condition. Leveraging the strong effects of the ZFYVE21 gene defect, we pair biochemical, functional, and in vivo approaches to understand new mechanisms by which ZFYVE21 contributes to human immune pathologies.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Despite the growing success of immunotherapies, such as chimeric antigen receptor-based cell therapy, cytokine therapy, and immune checkpoint blockade (ICB), a substantial number of cancers remain unresponsive. Furthermore, these therapies can lead to off-target toxicities, known as immune-related adverse events, resulting from overactivated immune cells. This project aims to devise a novel approach for deactivating regulatory T (Treg) cells, potent immunosuppressive cells in the tumor microenvironment, as a strategy to overcome immunotherapy resistance and minimize side effects. Preclinical studies in mouse models have demonstrated that depleting Treg cells can yield robust anti-tumor effects, even in tumors resistant to other forms of immunotherapy. However, current Treg-targeting therapeutics face significant challenges, particularly a lack of highly specific druggable targets and poor tumor selectivity. Our preliminary investigation into gene transcription regulation in Treg cells has yielded promising insights that could potentially address these obstacles. Using a genetically engineered mouse model for targeted protein degradation in vivo, we revisited the role of the Treg lineage-defining transcription factor Foxp3 in mature Treg cells post-developmentally. Contrary to expectations, Foxp3 was found to be largely dispensable for maintaining mature Treg cell identity and suppressor function. Instead, Foxp3 was uniquely essential for the heritability of Treg-specific gene expression and function across cell division. Consequently, hyperproliferative tumor Treg cells were much more dependent on Foxp3 for identity and function. Notably, degrading Foxp3 protein led to tumor shrinkage in a murine model of melanoma without overt toxicity. Building on these compelling results, we propose that Foxp3 protein degradation selectively inactivates tumor Treg cells, enhancing anti-tumor immunity with minimal extra-tumor adverse effects. We outline three aims to advance understanding and develop new reagents for this potential novel cancer immunotherapy option. Aim 1 involves characterizing the efficacy and adverse effects of Foxp3 degradation-based cancer immunotherapy. Aim 2 aims to elucidate the mechanisms of Foxp3 degradation-induced tumor killing. Aim 3 focuses on developing a chemical for degrading human Foxp3 protein, paving the way for therapeutic targeting of Treg cells in the clinical setting. Completion of these aims is anticipated to significantly advance our understanding of the efficacy, safety profile, and mechanism of action of Foxp3 degradation-based cancer immunotherapy. Moreover, the research aims to provide candidate compounds for further optimization, potentially offering new therapeutic options for cancer patients resistant to existing immunotherapies.

NIH Research Projects · FY 2026 · 2026-04

Peru's HIV epidemic is concentrated in MSM, where high rates of stigma and discriminaton toward them have undermined treatment outcomes. Despite high diagnostic and linkage rates, MSM have low levels of ART initiation and viral suppression related to low retention in care. For MSM with HIV, multi-dimensional stigma related to sexual orientation, substance use disorders, sex work, multiple sexual partners, etc. undermine treatment efforts through numerous clinical interactions that have the potential to reinforce stigma and delay ART initiation. This grant proposes a transformative approach to reduce HIV-related stigma through a Behavioral Design Intervention (BDI) that utilizes same-day ART (SD-ART) protocols to streamline the treatment initiation process. Unlike other stigma-reduction interventions, BDIs operate at the organizational level, rather than at the clinician or patient level. Our strategy builds upon robust evidence that rapid-start ART (RS-ART) significantly increases ART initiation, retention and viral suppression, thus improving individual and public health. To address the entrenched stigma and operational barriers that persist in treatment initiation, this research will deploy innovative methodologies and technologies. We will first develop a tailored SD-ART protocol utilizing asynchronous online focus groups and flowcharting techniques to map the current ART initiation process and design a streamlined SD-ART protocol. This protocol will use choice architecture to streamline the ART initiation process by minimizing clinical interactions that can reinforce stigma. Using nominal group techniques (NGT), a mixed methods strategy, we will assess multi-level barriers and facilitators to SD-ART from the perspectives of patients (MSM), clinicians, and administrators. From this process, scripts for framing and nudging will be created to inform refinements to the SD-ART protocol to ensure it addresses the specific needs of MSM and thereby enhancing its effectiveness and acceptability. The SD-ART protocol tailored to MSM using behavioral design will be pilot-tested with 125 newly diagnosed MSM. This phase will include longitudinal dyadic analyses to measure changes in stigma, physician trust, social support, and psychological well-being. These insights will not only assess the protocol's impact but also guide further improvements, paving the way for a future implementation trial. Our approach is distinctively designed to reduce the stigma experienced by MSM in clinical settings. By restructuring the decision-making process to prioritize clinical indicators over subjective assessments, our intervention aims to foster a more supportive and non-discriminatory healthcare environment. We hypothesize that this will decrease both perceived and enacted stigma, thereby improving patient-level health outcomes while reducing negative stereotypes by clinicians as MSM succeed in their treatment. By integrating behavioral design into the ART initiation trajectory, this project represents a novel approach to addressing the complex challenges of HIV treatment in high-stigma contexts, offering significant potential for replication and scalability elsewhere.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Neutrophils are essential mediators of antimicrobial defense but also instigate inflammatory injury and organ dysfunction. They are also endowed with protective features such as promoting revascularization or suppressing excessive immune activation. We have hypothesized that this heterogeneity of functions originates, in part, from the production of functionally different neutrophils from different granulocytic progenitors, thereby unveiling potential strategies to stimulate or prevent their anti-microbial, inflammatory, or reparative activities by targeting the different granulopoietic pathways. We have generated an integrative transcriptional map of the full neutrophil compartment in mice and humans which, when combined with computational modeling and fate mapping studies, revealed a novel granulopoietic path that produces a distinct population of CX3CR1+ neutrophils. In vivo profiling of these neutrophils reveals distinct phenotype, distribution in tissues and lifespan when compared with canonical neutrophils, suggesting fundamentally different biological properties of the two populations. Further preliminary studies indicate that these neutrophils acquire features of antigen-presenting and immunosuppressive cells, suggesting that the CX3CR1+ population is uniquely suited to modulate the response of the adaptive immune arm. In this proposal, we will examine the origin of CX3CR1+ neutrophils, the myeloid progenitors that produce them and the cytokines that control their production, whether these progenitors are different from those that produce canonical CX3CR1NEG neutrophils, and the preferred anatomical sites where these cells are produced (Aim 1). We will assess their capacity to capture antigen in vivo and to activate T cells through antigen presentation, or to suppress the cytotoxic activity of CD8 T cells, in the context of lung cancer and vaccinia infection. We will examine the specific contribution of GM-CSF and IFNβ, two cytokines that regulate homeostasis and inflammation, for the functional reprogramming and production of these immune-modulatory neutrophils (Aim 2). By defining a specialized maturation path that produces functionally distinct neutrophils, we will evaluate the potential of the granulocytic compartment for therapeutic manipulation.

NIH Research Projects · FY 2026 · 2026-04

Project summary Altruistic decisions, the act of benefiting others at a personal cost, are fundamental to social interaction and cooperation. However, the behavioral and neural mechanisms underlying altruistic decisions remain largely underexplored. This project aims to investigate how individuals evaluate costs and rewards to make altruistic decisions, focusing on the medial prefrontal cortex (MPFC) and its interaction with the striatum. Using an ethologically relevant model system that offers unique advantages due to its cooperative social behaviors and accessible neural recordings, I will study altruistic decisions in both cooperative and competitive contexts. In Aim 1, I will examine how varying physical costs influence altruistic behaviors in cooperative tasks. Behavioral and neural data will be analyzed to understand how the MPFC integrates self and partner effort levels to guide decisions. Aim 2 will explore altruistic decisions in competitive contexts by manipulating reward inequity, focusing on how the MPFC supports selfish and altruistic strategies and how reward size differences modulate these dynamics. Aim 3 will focus on the MPFC-striatal circuit, investigating its role in altruistic decisions using wireless high-density neural recordings and biologically constrained multi-area recurrent neural network models. These models will replicate behavioral and neural data from experimental work, generate testable hypotheses, and allow causal manipulation of circuit properties. By integrating naturalistic behavioral paradigms, advanced neural recording techniques, and computational modeling, this research will uncover the neural computations and circuitry underlying strategic altruism. The findings will significantly advance our understanding of prosocial decision-making and have broad implications for addressing psychiatric disorders with social deficits, such as autism spectrum disorder (ASD) and schizophrenia. This work aligns with my long-term career goal of establishing an independent research program that bridges experimental and computational neuroscience to study the neural basis of strategic prosocial behaviors and contribute to translational research on social dysfunction.

NIH Research Projects · FY 2026 · 2026-04

Project Abstract There have been numerous recent outbreaks of HIV among people who use drugs (PWUD) creating a “converging public health crisis” that threatens the success of the federal Ending the HIV Epidemic initiative. No single prevention or treatment approach will end the HIV epidemic among PWUD requiring new ways to bring services directly to PWUD where they are. This inspired the creation of the first legalized mobile pharmacy and clinic (MPC) health system in the U.S. with community health workers (CHW) working on the ground as one such strategy. However, knowing exactly where to go and how people will uptake services is still a vexing problem. Thus, we propose GEO IMPACT with an overarching goal of: Can a learning public health system be developed to increase reach and access to care for PWUD and who are living with or at risk for HIV? To reach this high-risk high-reward goal, the strategy is 3 fold: 1) Identify the population in need: With a first time-ever collaboration of 6 CT state health agencies, community groups, and researchers, we will identify the PWUD population living with or at risk HIV and quantify the magnitude of need for prevention and treatment services using modeling techniques.; 2) Align the need with access to services: With ongoing multidirectional data with CT state agencies, community HIV, SUD, and social service partners, and the MPC we will use the data to deploy the MPC to these areas and evaluate its impacts compared with matched communities on outcomes at 3 levels: macro (modeling and existing state markers of substance use and HIV), meso (community services and access to care) and micro (PWUD living with or at risk for HIV). A mixed-methods community engaged approach will characterize additional local barriers to optimize healthcare delivery and; 3) Use modeling and implementation information to make measurement-based improvement over three phases: Within the meta-framework of the Implementation Research Logic Model (IRLM), we will examine how the modeling information and the MPC intervention are working. Using mixed methods approaches, we will evaluate contextual determinants (barriers and facilitators) that mediate or moderate the achievement of these goals, the implementation strategies designed to achieve them, and if and how these implementation outcomes are being achieved. Akin to a learning health system approach, over three phases, we track how modeling and MPC services are working. With each subsequent phase we make iterative adaptations and improvements. This study combines a unique and broad set of methods and expertise, from the quantitative (spatial statistics, epidemiology and geography) to the clinical and operational (MPC), and implementation science. It is also multi-sectoral with 6 state agencies that will now collaborate with community and research partners on the health of PWUD. GEO-IMPACT is a radical approach that leverages: 1) the latest methods to identify PWUD at risk/living with HIV; 2) assertive mobile pharmacy and primary care and community health worker outreach service provision; and 3) a learning public health system to evaluate and improve how these innovative processes impact the lives of PWUD at risk and living with HIV.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract A versatile drug delivery platform of bioadhesive (BNPs) and non-adhesive (NNPs) biodegradable nanoparticles are engineered with unique properties for selective locoregional delivery of cytotoxic and immune conditioning agents to tumor cells, the tumor microenvironment (TME), and tumor draining lymph nodes (DLN). Features of BNPs (e.g. increased tumor retention) and NNPs (e.g. enhanced DLN accumulation) will be leveraged for the optimized locoregional treatment of advanced malignant melanoma. Further innovation in the delivery platform will be engineered by selectively modifying the NP core to enable mRNA incorporation and delivery and improve these therapies for melanoma and other cancers. Using mouse models recapitulating clinical settings of advanced melanoma, we will study comprehensively the induced immunologic effects within the TME and DLN, and abscopal effects on untreated skin tumors and hematogenously-spread metastatic lesions. We hypothesize that a multi-armed strategy of locoregional delivery in pre-clinical models of locally advanced (stage III) and metastatic (stage IV) melanoma—utilizing our next-generation BNPs and NNPs engineered for the efficient delivery of anti-tumor cytotoxic agents in combination with locoregional immune conditioning—will markedly limit melanoma tumor growth while also synergizing with systemic immune checkpoint inhibitors. We will test this hypothesis in three aims: (1) Assess the capacity of intratumoral delivery of BNP-anti-tumor and NNP- immunomodulatory agents to limit melanoma tumors and facilitate anti-melanoma immunity. Specifically, intratumoral delivery of BNP-exatecan, with and without co-delivered NNP-RG108 or NNP-MPLA, which we have engineered to accumulate in DLN and boost anti-tumor responses, will be tested in YUMM1.7-OVA (with tetramer tracking) and YUMMER1.7 melanoma models. We will assess local (TME, DLN) and systemic anti-tumor immune effects, including abscopal effects on a distant untreated tumor. (2) Develop next-generation locoregional immune enhancing BNPs by engineering incorporation of mRNA (IL-12) into the particle core. By engineering poly(amine-co-ester) (PACE) cores, BNP encapsulating IL-12 mRNA will be developed to enhance uptake by local DC populations and compared to lipid nanoparticle delivery. We will measure the degree to which select BNP-cytotoxic/NNP-DLN conditioning combinations can be enhanced by co-delivery with TME conditioning BNP-IL-12 mRNA, and use TotalSeq-C mouse CiteSeq scRNAseq/TCRseq with BaseScope and DBiTseq to identify tumor specific cells, TME transcriptional changes and spatial organization to better understand locoregional strategies. (3) Assess the capacity of systemically administered immune checkpoint inhibition to augment the anti-tumor effects of intratumoral BNP-cytotoxic agents, with and without BNP/NNP co- delivered local immune conditioning agents, to optimally treat melanoma tumors and limit metastatic melanoma. Through completion of these aims, we will advance our control of locoregional therapies for melanoma, and prepare for translation of these technologies to human melanoma patients.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT- Urinary incontinence (UI) is a common condition that affects up to 60% of women in their lifetime and is more prevalent among patients with obesity and Type 2 diabetes mellitus (T2DM). UI, obesity, and T2DM share a bidirectional relationship where UI limits exercise essential for managing obesity and T2DM, while both conditions exacerbate UI severity. Evidence-based UI treatments include lifestyle changes and medications that can be offered in any clinical setting, yet only 15% of individuals with UI seek treatment due to shame and barriers to care. Healthcare burden (e.g., multiple appointments, varying clinicians) further complicates care. These challenges emphasize opportunities to combine care for these diagnoses and improve care access and treatment outcomes for all three conditions. Collaborative Care Models (CoCM) have demonstrated efficacy for treating chronic conditions in primary care settings while minimizing treatment burden. Prior research has highlighted successes and challenges of offering UI treatment in primary care settings, but there are research gaps in assessing implementation of UI care among women with obesity and T2DM. Patient preferences have not been systematically evaluated and applied to implementation solutions, and CoCMs have not been studied for UI specifically. Therefore, among women with obesity and T2DM with UI, our Specific Aims are to: (1) assess patient preferences for obtaining UI care in primary care settings using mixed methods with survey assessment (n=100) that will inform guides for interviews (n≈12-20) and integration of data; (2) design a patient-centered CoCM for UI with involvement of stakeholders using participatory design and the Integrated Promoting Action on Research Implementation in Health Services (iPARIHS) Framework; and (3) evaluate the feasibility, acceptability, and preliminary effectiveness of this CoCM for managing UI through pilot implementation for 6 months with n=30 patients in a primary care clinic treating women with obesity and T2DM. This research will be conducted at a large Federally Qualified Health Center (FQHC), where I serve as the only urogynecologist providing care to a population that mirrors US demographics. As a committed physician with training and experience in community-based research, I am uniquely suited to carry out this project. This intervention has potential to transform care by addressing three prevalent conditions through an integrated approach that may improve outcomes for all three conditions while reducing treatment burden. This K23 award will support my development as an independent investigator through training in: (1) mixed-methods research; (2) design of interventions using dissemination and implementation science principles; and (3) clinical trials. Through coursework, research experiences, and mentorship from experts in mixed methods, implementation science, biostatistics and clinical trials, I will be poised to become an independent investigator who is a leader in the design and implementation of novel strategies to address pelvic floor disorders and improve the health of women with obesity and T2DM.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Substance use disorders (SUD) pose a major public health crisis that exacts heavy tolls on communities and healthcare systems, yet current survey data remain underutilized due to limitations in conventional analytic methods. This project proposes to develop a novel behavioral foundation model that transforms qualitative epidemiological survey responses into robust, quantitative latent representations of substance use behaviors. By harmonizing data from NESARC-III, NSDUH, and UK Biobank, we will “textualize” both structured and free- text responses into unified narratives that capture the nuanced details of individual experiences. Our approach leverages advanced natural language processing to convert diverse survey data into coherent, machine- interpretable inputs, and fine-tunes state-of-the-art, open-source large language models (LLMs) with integrated demographic tokens to enhance subgroup-specific predictions. We will rigorously validate the model’s performance against established machine learning techniques using metrics such as area under the ROC curve, calibration, and cross-dataset generalizability. Downstream applications include precise risk stratification for SUD outcomes, latent clustering to identify distinct risk and resilience profiles, and data-driven survey instrument optimization. Open-access dissemination of our tools will empower precision public health initiatives, enhance early identification of high-risk groups, and support targeted interventions to reduce the societal burden of substance use disorders.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a nuclear localized dual specificity phosphatase that dephosphorylates the regulatory tyrosine and threonine residues in the activation loop of MAPKs. MKP-1 preferentially dephosphorylates the nuclear pool of JNK1/2 and p38 MAPK and is found to play significant regulatory roles in metabolism. It is found to be upregulated in the liver of mice fed a high fat diet (HFD) and in obese human. Given the significant increase in liver disease as a result of obesity, understanding the mechanisms of aberrant MKP-1 signaling on liver metabolism is important. This is supported by liver-specific deletion of MKP-1 (MKP-1 LKO), which protects against hepatic steatosis. These observations raise the exciting possibility that MKP-1 can be targeted for the treatment of metabolic associated steatotic dysfunction liver disease (MASLD). Although MKP-1 represents an attractive target for pharmacological inhibition it has been considered largely ‘undruggable’ partly due to the high similarity between PTP active sites and the propensity for active site compound selection, which often leads to charged compounds hits with poor bioavailability. Our lab has recently developed specific allosteric inhibitors for MKP-5. These inhibitors bind to a previously undescribed allosteric site within the catalytic domain. Mutation of the allosteric site dramatically inhibits MKP-5 catalysis and serves as a docking site for MAPK. This site is highly conserved amongst all active MKPs, including MKP-1, suggesting that it has an essential conserved role for catalysis. Therefore, I hypothesize that the MKP-1 allosteric site is critical for the regulation of its catalytic activity and binding to MAPKs, and that this site represents a target for the development of allosteric small molecule inhibitors for the treatment of MASLD.

NIH Research Projects · FY 2026 · 2026-04

Implantation is a critical process in human development, initiated when the blastocyst-stage embryo establishes contact with the maternal endometrium. This interaction is mediated by trophoblast cells from the trophectoderm, which regulate early invasion and maternal-fetal crosstalk. Disruptions in trophoblast- endometrium interactions can lead to implantation failure, pregnancy loss, and complications such as preeclampsia. Women with endometriosis, a systemic condition affecting millions in the U.S., face an increased risk of infertility and pregnancy complications. However, the molecular mechanisms underlying these issues remain poorly understood, highlighting the need for models that accurately replicate trophoblast-endometrium dynamics in both healthy and diseased states. Existing in vitro models lack critical architectural and functional features, limiting their translational relevance. To address this gap, I developed a novel patient-derived 3D EndoMetrial Assembloid (EMA) that mimics key aspects of endometrial architecture, including epithelial, stromal, and uterine endothelial cells; hormone responsiveness; basement membrane secretion; and apical-out polarity. This platform enables physiologically relevant studies of trophoblast-endometrium interactions. This proposal will investigate the role of miRNAs in decidualization within the context of endometriosis, and how the disease affects trophoblast development and invasion. I propose to integrate advanced 3D tissue engineering, high-resolution imaging, extracellular vesicle analysis, and transcriptomic/functional assays to explore how endometriosis-associated decidualization defects influence trophoblast behavior. This study will provide insights into the mechanisms driving implantation defects and pregnancy complications by addressing fundamental questions about trophoblast-endometrium interactions in the context of endometriosis. Ultimately, these findings will be critical for the possible prevention of adverse pregnancy outcomes, offering a unique opportunity to inform future diagnostic and therapeutic strategies for improving reproductive outcomes in endometriosis patients.

NIH Research Projects · FY 2026 · 2026-04

Project Summary This proposal aims to investigate the activation process of an unusual receptor tyrosine kinase (RTK) called ROS1. ROS1 plays important roles in various aspects of development and disease, including fertility, heart disease, and cancer. Unlike other RTK families, ROS1 receptors have a unique structure and the largest extracellular region (ECR) with predicted domains not found in any other RTK. However, the structure and regulation of ROS1 are still not well understood. This lack of understanding is partly due to the absence of a cell- based system to study its function and limited accessibility to structural and biophysical analysis due to its large ECR. We have overcome these obstacles and now plan to reveal the molecular mechanisms regulating ROS1 activation. Our goals for the next 10 years are to: 1) Gain a comprehensive understanding of how ROS1 receptors sense and transmit signals from their extracellular environment, 2) Investigate how receptor mutations and changes in the cellular matrix affect ROS1 signaling in disease, and 3) Explore whether the unique structural and regulatory elements of ROS1 could serve as novel targets for therapeutic interventions. Our research will involve studying the biochemical and structural aspects of ligand-receptor complexes to uncover how ligand binding leads to ROS1 activation in the signaling complex. By doing so, we aim to provide crucial insights into the signaling process of this distinct receptor family that deviates from the conventional RTK paradigm. This understanding will be essential for the development of effective inhibitors that target ROS1 specifically, as well as for devising clinical strategies to address ROS1-related diseases and their associated mutations.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Post-traumatic epilepsy (PTE) affects nearly 400,000 patients in the US each year significantly impairing recovery and increasing psychological and financial burdens. Despite its profound impact, strategies for PTE prevention and prediction remain elusive, with current risk models hindered by their ability to scale to larger health systems or populations, reliance on data that is not readily available to the broad traumatic brain injured population or the need for labor-intensive extraction of important variables from the clinical heath record. These limitations restrict applicability of existing models to broader patient populations and exacerbate health disparities. This project aims to overcome these barriers by developing automated, scalable, and clinically applicable tools for PTE risk stratification. Our central hypothesis is that automated extraction and analysis of multidimensional clinical and imaging data can identify high-risk PTE patients, enabling early intervention and enhancing treatment feasibility. We will leverage advances in machine learning, natural language processing, and neuroimaging to analyze data from approximately 3,000 TBI survivors, addressing three specific aims: (1) Optimize Automated EHR Phenotyping: Develop an algorithm to retrospectively identify PTE patients to more easily identify a large cohort of PTE patient for future PTE risk prediction models and to use electronic health record (EHR) data from the first seven days post-TBI to predict future PTE risk. We will analyze structured and unstructured data to uncover novel predictors and word clusters indicative of PTE risk. (2) Quantify Contusion Features with Deep Learning: Implement a convolutional neural network (CNN) to automatically measure contusion volumes and locations from acute CT scans to assess their predictive value for PTE risk. (3) Evaluate Cortical Volume and Thickness from MRI: Use CNN-based segmentation of clinical MRI scans to analyze cortical volume and thickness to explore their association with PTE. As a final Exploratory Aim, we will integrate the features from these aims into a unified prediction model, hypothesizing that a comprehensive approach will outperform single-modality models. This work has the potential to transform PTE risk prediction by leveraging widely available clinical data and automated tools, providing a foundation for more effective diagnosis, prevention, and treatment strategies across diverse healthcare environments.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Epidemiological evidence links peripheral inflammation to an increased risk of dementia, yet the mechanisms underlying this association remain unclear. Although peripheral immune challenges can amplify neuroinflammation and accelerate cognitive decline, we still do not understand the thresholds required to elicit neuroinflammatory responses that alter neuronal activity, their underlying cellular mechanisms, or how these thresholds and mechanisms change with age. This gap stems from viewing neurons as a passive recipient of neuroinflammatory signals, but also from the use of models with limited relevance. Our long-term goal is to understand how peripheral inflammation interacts with aging to increase the risk of dementia. Prior studies showed that aging sensitizes microglia, making them highly responsive to immune signals and driving exaggerated responses that disrupt synaptic circuits and lead to cognitive deficits. Furthermore, increasing evidence-including our preliminary data-indicates that peripheral inflammation can also directly alter neuronal activity and connectivity. Our proposal builds on this foundation and advances a novel hypothesis: while chronic inflammation directly activates microglia, in acute inflammation, the flow of events begins with neurons. Our preliminary data show that acute inflammation initially alters the activity of inhibitory neurons in key cortical regions. This change may then be detected by microglia, which respond according to their current, age-dependent state by further altering inhibitory synapses and the excitation-inhibition balance. To test this hypothesis, we will use mouse models that mimic common human inflammatory conditions: house dust mite (HDM}-induced respiratory allergy and dextran sulfate sodium (DSS}-induced colitis. Aim 1 will define microglia responses to acute and chronic inflammation as a function of age and will assess whether T cells contribute to increased responses of microglia to acute inflammation in aged mice. Aim 2 will test whether changes in inhibitory activity following acute inflammation trigger microglia activation in aged mice and will define the associated microglial molecular responses. Aim 3 will examine if microglia respond to changes in inhibitory activity by further altering cortical circuits in an age-specific manner. With expertise in molecular, cellular, and circuit neuroscience, inflammation, and imaging, our team is uniquely positioned to carry out this interdisciplinary project. The Pl's past discovery of specific microglia-inhibitory neuron interactions is an additional strength. We will use an innovative approach that combines relevant mouse models, advanced immunological techniques (e.g., adoptive transfer, immune cell depletion), and state-of-the-art neuroscience methods (e.g., calcium imaging, chemogenetics) to test our hypothesis. This research addresses a significant biomedical challenge-understanding how peripheral inflammation affects the aging brain-and has the potential to transform our understanding of neuroimmune interactions in dementia. We will identify key features of microglia-PV neuron interactions following peripheral inflammation and define how they shift with aging. Ultimately, our findings could reveal age-specific therapeutic strategies to reduce the risk of dementia.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Malformations of cortical development (MCDs) are neurological disorders characterized by altered organization and function of cortical neurons, often leading to intractable epileptic seizures. Somatic mutations in more than 60 genes have been found in MCDs, with pathogenic variants causing focal impairment of cortical function. This genetic heterogeneity is reflected in the delineation of multiple types of MCDs, including focal cortical dysplasia type I (FCDI) and type II (FCDII) and Tuberous Sclerosis Complex (TSC). These MCD classes have overlapping and distinct genetic bases and cortical neuron phenotypes. For example, FCDII and TSC exhibit hyperactive mTORC1 signaling due to activating mutations in pathway components (or inactivating mutations in negative regulators such as TSC1 and TSC2), while FCDI does not exhibit mTORC1 alteration. Critically, the mechanisms by which MCD-associated mutations drive disease pathogenesis remain incompletely understood, and the degree to which these mechanisms are shared across MCD types is unclear. Better understanding the basis of MCDs promises to not only shed light on the fundamental biology of cortical development, but also to offer improved diagnostic tools and therapeutic strategies for MCD patients. Here, we propose a new model for MCD pathogenesis based on our recent finding that dysregulation of primary cilia is a shared feature of gene variants responsible for FCDI, FCDII, and TSC. This model is based upon the convergence of two unbiased genetic studies: a consortium-led sequencing study that identified 69 genes mutated in MCD patients and a genome-wide CRISPR activation screen we conducted that identified a novel pathway for cilia disassembly. Based on the significant overlap of these gene sets and the established importance of cilia in cortical development, we hypothesize that aberrant disassembly of primary cilia is a shared pathological basis for MCDs. In support of this hypothesis, our preliminary data show that a FCDI- associated variant in SARM1 induces cilia loss, while Sarm1 inhibition restores cilia in cells harboring mutations in SARM1 or in FCDII gene TSC2. From these findings, several questions emerge, including: how does FCDI-associated mutation of SARM1 impact cilia and cortical development in vivo; what is the functional relationship between cilia loss induced by Sarm1 versus by mTORC1; can inhibition of cilia disassembly mitigate FCD-associated pathology; and do other ciliary regulators contribute to MCDs? We will address these questions in three aims: 1) test the effect of an FCDI-associated SARM1 variant on neuronal ciliation, cortical development, and seizure activity, 2) test the hypothesis that mutation of FCDII gene TSC2 alters neuronal development and function through Sarm1-mediated cilia disassembly, and 3) use CRISPR screening to define additional genes that promote cilia loss in MCD. These studies will be performed through a collaborative effort of the Breslow and Bordey labs that combines their unique and complementary expertise in cilia, ciliopathies, functional genomic screening, MCD pathogenesis, and murine cortical development and function.