New York University School Of Medicine

NIH Research Projects · FY 2026 · 2025-02

The long-term goal of this project is to validate plasma membrane vacuolar ATPase (pmVATPase) as a therapeutic target and to develop novel antibodies targeting pmVATPase as anti-cancer therapy. Vacuolar ATPase (V-ATPase) is a complex molecular machine that transports proton ions across organelle membranes or the plasma membrane. An increase in the abundance of pmVATPase are associated with KRAS-driven, challenging cancers, and it promotes tumor cell survival through multiple mechanisms. Currently available inhibitors against V-ATPase are not selective to pmVATPase because they are cell permeable and hence inhibit V-ATPase at intracellular membranes as well as pmVATPase. This lack of subcellular selectivity compromises V-ATPase functions that are crucial for normal cell functions such as endocytosis, lysosomal degradation and autophagy, leading to high toxicity. We propose to utilize antibodies, which are inherently cell impermeable, to achieve higher selectivity toward pmVATPase and to minimize toxicity. Early three-dimensional structures showed that pmVATPase has minimal exposure on the extracellular side of the plasma membrane, suggesting that pmVATPase is an extremely challenging antigen for developing antibodies. However, recent structures of complete mammalian V-ATPases revealed that the ATP6AP1 (also known as Ac45) subunit presents a sizeable globular domain on the extracellular surface. Unlike previously targeted subunits, ATP6AP1 is common in all populations of pmVATPase (harboring different subunit a isotypes) and crucial for localization of V-ATPase on the plasma membrane. Based on these data, we hypothesize that ATP6AP1 presents surfaces (epitopes) that are more accessible by antibodies, and that we can identify anti-ATP6AP1 antibodies that can selectively inhibit pmVATPase. We propose the following Aims. 1. We will develop anti-ATP6AP1 antibodies that recognize pmVATPase on cells. We have already produced a water-soluble form of the ATP6AP1 globular domain and generated a panel of antibodies against it, which has substantially de-risked this project. 2. We will develop a strategy to selectively inhibit or kill cancer cells that have high levels of pmVATPase with anti-ATP6AP1 antibodies. If successful, this project will establish pmVATPase as an actionable therapeutic target and advance development of novel therapeutics against multiple cancer types.

NIH Research Projects · FY 2026 · 2025-02

ABSTRACT Bone metastasis is a devastating consequence of cancer progression. In melanoma, almost 45% of metastatic patients will develop bone metastasis, with bone being the fourth most common site of metastasis after brain, liver, and lung. Once melanoma cells infiltrate the skeleton, the increased risk of skeletal related events— including bone fractures and pain—profoundly reduces quality of life. Melanoma patients who present with bone metastases have poorer responses to immune checkpoint blockade than patients who develop metastases in visceral organs or the brain. Evidence from multiple myeloma and both breast and prostate adenocarcinomas suggest the bone microenvironment (BMM) plays an important role in metastatic colonization. However, we know little about the mechanisms melanoma cells use to infiltrate and modify the skeleton, communicate with immune cells, and resist immunotherapy. This is in part due to the scarcity of preclinical models that truly recapitulate human melanoma bone metastasis. We have established preclinical murine models that recapitulate human melanoma bone metastasis. We will compare bones from these models to naïve, non-tumor bearing bone to define the mechanisms melanoma cells use to colonize the skeleton and modify the BMM. In these models, we have observed a higher number of reactive neutrophils (bone metastasis-associated neutrophils or BMANs), which express an IFNg-response signature characterized by high expression of a family of protease inhibitors called Stefins. Our proposed functional studies will reveal whether BMANs support melanoma cell adaptation to the bone parenchyma. Additional single-cell analyses, using both murine models and patient samples, will uncover at high resolution the interplay between tumor, skeletal, and immune cells during melanoma bone metastasis. The successful outcomes from this work will improve our understanding of how melanoma grows in bone and pave the way for better treatments for bone disease.

NIH Research Projects · FY 2026 · 2025-02

Project Summary Alzheimer's disease (AD) affects 6.7 million Americans. Extracellular deposition of E-amyloid (AE) and accumulation of hyperphosphorylated-tau inside neurons are two primary culprits of AD pathology and targets for emerging AD therapies. Recent clinical trials of anti-AE monoclonal antibodies (mAbs) in AD patients showed AE deposition can be reversed resulting in significant slowing of cognitive decline. Yet, anti-AE immunotherapy comes with several shortcomings. These include need for recurring mAb infusions, staggering costs, and serious side effects in the form of brain bleeds and/or edema, and contraindications disqualifying a large number of patients. Chimeric antigen receptor (CAR) therapies have recently revolutionized several areas of oncology and hold high promise for adaptation in other medical fields including neurodegeneration, where CAR-engineered macrophages (Mĭs) can be used for targeted clearance of disease specific misfolded proteins and modulating neuroinflammation. A key issue in CAR-based therapies are their high costs resulting from in vitro engineering of patient-derived T cells or Mĭs and subsequent autologous implantation. This can be addressed using HLA- compatible, “off-the-shelf” human induced pluripotent stem cells (hiPSCs) as a platform for expressing disease specific CARs. This R61/R33 application proposes to develop a unique CAR-Mĭ therapy for AD based on “off- the-shelf” hiPSCs, which will be genetically programmed for fast and robust transdifferentiation into self- sustainable, macrophages/microglia (iMĭ) expressing CARs targeting AD specific proteins. Our CAR-iMĭs will be engineered to withstand CSF1R inhibition , which will be used to facilitate their brain homing. They also will be modified for attenuated inflammatory response and equipped with “kill switches” for therapy control. Our preliminary work for this grant application includes identification of five novel anti-AE clones binding AE deposits and effecting their clearance in APP/H3 mice by Fc-mediated microglia phagocytosis. We also have engineered a doxycycline-inducible genetic circuit expressing SPI1 and CEBPĮ transcription factors allowing for robust trans- differentiation of hiPSCs into iMĭ. Aims of the R61 phase are as follows: 1) to optimize iMĭ transdifferentiation protocol and characterize resulting iMĭ cells; 2) to engineer CARAE using scFv sequences from our novel anti- AE clones and express them in iMĭs; 3) to engineer an orthogonal CSF1 receptor, which will be constitutively active and resilient to pharmacological inhibition; 4) to reprogram hiPSC HLA to “cloak” the cells against the intact murine immune system permitting in vivo testing. Aims of the R33 phase will be as follows: 1) to produce CARAE-iMĭs by combining all singular genetic elements tested in the R61 phase and characterize CARAE-iMĭ biodistribution, brain homing and survival in vivo; 2) to test engagement and clearance of AE plaques by CARAE- iMĭs in APP/H3 and APP/H4 mice; 3) to characterize the transcriptomic profile of CARAE-iMĭs in APP/H3 and APP/H4 mice and explore effects of knocking-out genes, which are key to acquisition of MGnD phenotype and propagating inflammatory response; 4) to engineer and test “kill switches” for on demand activity control.

NIH Research Projects · FY 2025 · 2025-02

PROJECT SUMMARY The proposed study aims to use a community-driven process to refine and pilot test a multi-level HIV prevention and wellness intervention designed to increase HIV testing by addressing intersectional stigma, focusing on Chinese immigrant female sex workers (FSWs) in New York City (NYC). This population is at significant risk for HIV but exhibits low HIV testing rates. Chinese immigrant FSWs face a convergence of multiple and intersecting stigmas and multiple structural vulnerabilities, which contributes to their low levels of HIV testing. Only a limited number of HIV interventions have explicitly targeted multi-level, intersectional stigma to increase HIV prevention behaviors, and none have specifically targeted Chinese immigrant FSWs and the providers who serve them. Accordingly, the proposed project (“Initiative for Chinese Sex workers to Promote wellbeing and Improve HIV prevention by Reducing intersEctional stigma” [INSPIRE]) aims to conduct a feasibility study of a culturally relevant, multi-level HIV prevention and wellness intervention designed to increase HIV testing through reducing intersectional stigma. The preliminary design of INSPIRE was developed based on the investigators’ extensive preliminary research with Chinese immigrant FSWs, principles of Social Action Theory, and elements of an existing evidence-based HIV prevention intervention for FSWs (Community Promise). To prepare INSPIRE for pilot-testing, we propose the following complementary components: 1. At the individual-level, use a community-driven process to further refine INSPIRE’s design and optimize it with intersectional stigma components; 2. At the institutional-level, incorporating key elements of stigma-reduction outlined by Nyblade and colleagues, develop an anti-stigma training for providers to create a welcoming environment for FSWs who, encouraged by the individual-level component, decide to seek out the health services they need. The Specific Aims of INSPIRE are to: Aim 1: Using the ADAPT-ITT model, refine and stigma-optimize INSPIRE, a multi-level culturally relevant HIV prevention and wellness intervention for Chinese immigrant FSWs designed to increase HIV testing by addressing individual-level (internalized) and institutional-level (healthcare providers) intersectional stigma; Aim 2: Conduct a pilot randomized controlled trial of INSPIRE to gather necessary information for developing a full-scale trial; Aim 3: Systematically assess the feasibility, acceptability, and barriers to/facilitators of implementing INSPIRE using mixed methods and guided by the intersectionality-enhanced CFIR. By developing and testing an innovative, culturally relevant HIV testing intervention that addresses intersectional stigma, the proposed study will make substantial contributions to reducing HIV risk in this highly vulnerable, under-served, and under-researched population.

NIH Research Projects · FY 2026 · 2025-01

SUMMARY Transdifferentiation is a common mode of cellular plasticity in resistance to targeted therapy, and is observed histologically across multiple cancer types, including LUAD-to-small-cell lung cancer, enabling resistance to EGFR inhibitors. There is a growing recognition that the adaptive process taken by cancer to thwart therapy has a non-genetic component, thus requiring the determination of new avenues of therapy. In LUAD, KRAS was long thought to be undruggable, however, two inhibitors received FDA approval three years ago. Though these inhibitors contributed to a response rate of 40% improving clinical outcomes, patients inevitably relapse, with a subset of the tumors adapting to KRAS inhibition by non-genetic mechanisms. In 2020, members of our team discovered that in response to one of the KRAS inhibitors – adagrasib – the tumors of a subset of patients undergo an adeno-to-squamous transition (AST). In this proposal we formulate a comprehensive research program aimed at dismantling AST as an escape route for cancer to adagrasib treatment, by blocking its required chromatin regulators and by decoupling it from the induction of resistance programs. In our preliminary studies, we established mouse and organoid models and found evidence that disruption of specific chromatin regulators either genetically or pharmacologically modulates cellular state along the AST spectrum. This has led us to hypothesize that a screen of chromatin remodelers will reveal AST vulnerabilities. In Aim 1, we carry out a Perturb-Seq screen coupled with a scMultiome approach to identify the specific regulators and then target these with small molecule inhibitors. Finally, we test the translational potential of these inhibitors to block the transition in human patient derived xenografts. A second major finding that we address here is that the squamous histology alone is not sufficient to confer drug resistance to adagrasib, suggesting that additional molecular pathways are required for the adaptive process. This has led us to hypothesize that drug resistance is caused by the sequential induction of first the resistance programs and then a lineage state transition. A prediction of this hypothesis is that distinct lineage states are compatible with unique resistance programs, and thus we seek to systematically decouple this relationship to reveal the specific dependencies of each lineage state. In Aim 2, we leverage a dropout CRISPR-method approach to identify regulators of resistance for both the intermediate and the squamous lineage state along AST, and then we systematically test for the sufficiency and necessity of both the lineage state and resistance programs in modulating the response to KRAS inhibition. We then more broadly test for the expression and clinical relevance of resistance programs in primary human lung adenocarcinoma tumors and how they relate to the host lineage states. Overall the impact of this research is to identify new therapeutic vulnerabilities of lineage states along AST – an important and unaddressed clinical problem – by dissecting the relationship between lineage state and resistance programs.

NIH Research Projects · FY 2025 · 2025-01

PROJECT SUMMARY/ABSTRACT Acute respiratory failure (ARF) requiring invasive ventilation occurs in one-third of intensive care unit (ICU) patients and is associated with a high risk of death. Ventilation-induced lung injury (VILI) is a modifiable determinant of ARF outcomes that develops when the at-risk lung experiences excessive global or regional stress/strain. VILI may result from excessive forces applied by the ventilator and/or respiratory muscles. Optimizing ventilator titration has been studied extensively, while far less is known about the contribution of spontaneous breathing effort to VILI in ARF. High respiratory drive can cause injuriously high tidal volumes, increasing global stress/strain either with synchronous effort or breath stacking dyssynchrony depending on ventilator mode. High drive also causes temporally heterogeneous insufflation, increasing intra-tidal regional strain for a given tidal volume. Both patterns of respiratory drive-related increase in stress/strain worsen lung injury in preclinical models and have been observed in patients with ARF, but whether they contribute clinically meaningful lung injury in patients is unclear. Extremes of drive, high or low, also may cause clinically relevant diaphragm injury. High drive risks load-induced injury, particularly in flow-limited ventilator modes or certain patient-ventilator dyssynchronies in which inspiratory support ends prematurely relative to patient effort. Low drive risks diaphragm disuse atrophy, proven to occur in some patients within a few days on the ventilator. Causes of drive heterogeneity in ARF are not well established. Chemoreceptor, mechanoreceptor, and cortical inputs (e.g. pain, anxiety) are well established modulators of respiratory drive, but they alone do not fully explain drive heterogeneity in ARF. Although deep sedation often suppresses respiratory drive in healthy individuals, we recently found that sedation depth and respiratory drive are not well correlated in ARF. Many patients exhibit high drive refractory to deep sedation, while in others even light sedation can completely eliminate drive. Our preliminary data suggest differences in systemic inflammation might explain this drive heterogeneity. This research will deepen understanding of mechanisms underlying drive heterogeneity and its relationship with clinical outcomes in patients with ARF. Our overall hypothesis is that systemic inflammation is a key determinant of respiratory drive, extremes of which cause clinically important lung and diaphragm injury. We will assemble a prospective two-hospital, multi-ICU cohort in whom respiratory mechanics and serum biomarkers are ascertained serially. Aim 1 evaluates circulating inflammatory markers as a potential contributor to drive heterogeneity. Aim 2 determines mechanisms by which extremes of respiratory drive may contribute to lung and diaphragm injury. Aim 3 evaluates the relationship between respiratory drive and time to extubation. Findings from this work will inform development of a precision ventilation strategy, incorporating respiratory drive to optimize lung and diaphragm protection, for evaluation in a future clinical trial.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT The overarching goals of this K23 proposal are to improve understanding of the role played by the autonomic nervous system (ANS) in the cardiovascular (CV) complications of chronic kidney disease (CKD) and to facilitate the career development of the candidate, Qandeel Soomro MD, MS, a Nephrologist in the Division of Nephrology at the NYU Grossman School of Medicine. Through a mentored training and research experience, the candidate will develop the requisite skills and preliminary data needed to become an independent researcher investigating autonomic physiology in the setting of CKD and testing interventions to prevent the CV sequelae of ANS dysfunction in this setting. The five-year plan includes in-depth training and didactics in ANS function testing, causal inference methods, and clinical trial design and operations under the primary mentorship of David Charytan MD, MSc. CV autonomic dysfunction is an important contributor to cardiovascular morbidity and mortality in the general population and has been implicated in the strong association of kidney and heart disease. However, prior studies in the setting of CKD have not investigated the potential causes of ANS dysfunction, have focused solely on evaluating sympathetic hyperactivity, have limited ANS interrogation to testing of heart rate variability data, failed to adequately account for the effects of diabetes, and have had limited sample size and focused solely on dialysis-requiring end stage kidney disease. This incomplete characterization has limited understanding and the development of diagnostic tools or targeted therapies that could improve CV outcomes in this high-risk population. Our overarching hypotheses are that ANS function worsens with decline in kidney function with the phenotype shifting from a predominantly parasympathetic dysfunction in early stages of CKD to a sympathetic one in more advanced CKD, that inflammation is a key mediator of ANS dysfunction, and that non-invasive vagal stimulation will substantially improve ANS dysfunction. Three specific aims are proposed: 1) Deeply phenotype autonomic dysfunction in CKD using a comprehensive battery of tests longitudinally and cross-sectionally; 2) Quantify the association of inflammation and autonomic dysfunction in CKD using causal inference methods; and 3) Perform a pilot trial of trans-auricular vagal nerve stimulation to improve ANS function in CKD. Results from this proposal will improve understanding of ANS function in CKD, provide initial feasibility and safety data on a novel therapeutic option, and inform the design of interventional studies to reduce the burden of CV disease and mortality in a highly vulnerable population. Completion of this K award, will position the candidate for her long- term goals of improving the lives of patients with CKD by conducting independent investigations into the physiology and treatment of CV disease in CKD.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract A Novel Open-Source Optimization Framework for the Design and Simulation of Radiofrequency Coils for Magnetic Resonance Imaging Radiofrequency (RF) coils are essential in magnetic resonance imaging (MRI) because they affect the obtainable spatial and temporal resolution, the image homogeneity, and the encoding capability for parallel imaging, among other things. One limitation of the current approach to coil design is that the quality of a coil can only be compared against other available coils, giving no indication of whether there is room for further improvement beyond the best-performing design tested. Theoretical coil performance limits have been proposed as both absolute references to assess any coil design and target metrics for coil design optimization. The goal of this project is to develop and demonstrate a novel shape optimization approach for the design of RF coils based on ultimate performance benchmarks. This project will introduce a new method for rational coil design that relies on rapid volume-surface integral equation techniques to simulate the coils’ RF fields and advanced shape modeling algorithms to automatically explore geometric variations and find the optimal design. Starting from a target anatomical model, a coil substrate tailored to it, and a desired number of channels, our software toolkit will automatically optimize shape, position and geometric arrangement of the coil elements of an array to minimize the deviation of the simulated performance from the corresponding theoretical performance limit. This project will build upon computational electromagnetics methods recently introduced by our group for ultra-fast coil simulations and the calculation of ideal current patterns associated with optimal performance (ultimate intrinsic signal-to-noise ratio and ultimate intrinsic transmit efficiency) in realistic anatomical models. We will also rely on the extensive expertise of the project team with automatic mesh generation and shape optimization with adjoint- based gradient computation. We will validate the proposed coil design optimization framework in simulations and experiments. In particular, we will model, simulate, and then construct a flexible receive array for knee imaging at 3 tesla (T) and a 7 T transmit-receive head and neck coil. We will distribute all software as open source and fully documented, including tutorials and examples.

NIH Research Projects · FY 2026 · 2025-01

Project Summary The broad, long-term objectives of this application are to characterize mechanisms that allow a competitive germline stem cell (GSC) and its descendants to dominate the GSC population and cause super-Mendelian inheritance. The proposal will determine how a GSC in the Drosophila testis remodels its niche and causes the selective loss of WT neighbor GSCs. To accomplish this, the proposal will utilize immunofluorescence, genetics, RNA interference, extended ex vivo live-cell imaging, transcriptomics, chromatin labelling, and innovative assays of GSC competition and allele inheritance in F1 offspring. We will capitalize upon the powerful genetics available in Drosophila, as well as the ability to unequivocally identify the niche, GSCs, differentiating germline cells, and somatic stem cells (CySCs) and their lineage in the Drosophila testes. This proposal is supported by our published results demonstrating that (1) loss of the transcription factor Chinmo in a GSC causes the ectopic secretion of the extracellular matrix (ECM) protein Perlecan (Pcan), (2) this Pcan accumulates around the endogenous niche resulting in an ectopic ECM termed the moat within the testis lumen; (3) the moat causes the selective loss of WT neighbor GSCs, which no longer have strong adhesion with niche cells; (4) chinmo-/- GSCs remain in the resculpted niche because they upregulate ECM-binding proteins. This proposal is also supported by our unpublished results showing that Chinmo protein expression is promoted by an RNA-binding protein (RBP) in GSCs and that a ZAD-ZNF protein likely acts as a Chinmo co-factor in GSCs. In the first goal, we will determine whether clonal loss of the RBP that promotes Chinmo expression imparts that GSC with a competitive advantage. We will also determine what regulates that RBP in GSCs and test whether loss of any regulators of the RBP imparts a competitive advantage to a mutant GSC. In the second goal, we will determine whether Chinmo and the ZAD-ZNF protein work together to repress Pcan by recruiting histone methyltransferases. We will also determine how niche cells promote the ectopic Pcan produced by chinmo-/- GSCs. In the third goal, we will test the role of somatic stem cells (CySCs) in GSC competition and assess whether they push out WT neighbors GSCs. We will also use live-cell imaging to determine the types of GSC division that occur in chinmo- /- GSCs. The studies in this proposal will increase the knowledge base about GSC competition and will foster new avenues of research into mechanisms and possible treatments for human paternal age effect disorders caused by competitive spermatogonial stem cells and for tumor cells which remodel their microenvironment to benefit themselves and disadvantage WT neighboring cells.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease defined by the widespread accumulation of hyperphosphorylated tau (p-tau) in perivascular spaces and by regional brain atrophy. Athletes engaged in contact or collision sports, like American football players, are at a heightened risk for developing neurological disorders including CTE given their extensive exposure to repetitive head impacts (RHI). The neuropathology of CTE at postmortem is well established, however, there are currently no biomarkers available to diagnose CTE during life. There is only a classification of clinical symptoms associated with presumed CTE, called Traumatic Encephalopathy Syndrome (TES), in which the diagnosis is solely based on exposure to RHI and core clinical features of cognitive impairment and/or neurobehavioral dysregulation. Therefore, there is an immediate need to develop precise methods that can either support the clinical diagnosis of TES or detect and diagnose CTE during an individual's lifetime, enabling the development of suitable treatments and interventions. Thus, the primary objective of the current proposal is to study the long-term consequences of RHI in former athletes, particularly, former American football players. We will leverage data from the NINDS-funded Diagnostics, Imaging, And Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project (U01NS093334), which includes behavioral, neuroimaging, and fluid biomarker data from 180 former American football players (60 former college players, and 120 former professional players) and a control group of 60 unexposed asymptomatic controls who are age-matched and have no history of RHI exposure or traumatic brain injury. We will utilize structural magnetic resonance imaging (MRI) to investigate neuroanatomical changes linked to neuropathological alterations observed in CTE at post-mortem. This investigation includes examining morphological changes in the sulci, ventricles, and gray/white matter. Furthermore, we will investigate aspects of the brain's waste clearance pathway by identifying changes and associations in structures important for this function such as the ventricles, choroid plexus, and perivascular spaces. This investigation provides insights into the accumulation of p-tau in perivascular spaces, a hallmark of CTE typically reported in post- mortem cases. In our design, we will include factors likely to contribute to worse outcomes within our neuroimaging measures by attempting to find associations with age, exposure factors (age of first exposure to football, total years playing football, and estimates of head impact), known contributors of CTE pathology (global p-tau aggregation), and TES diagnosis. Ultimately, understanding the presentation of neuroanatomical abnormalities and underlying mechanisms relating to p-tau accumulation could lead to supportive features for TES and possible biomarkers for the early detection of CTE during life.

NIH Research Projects · FY 2026 · 2025-01

Vision impairment impacts ~60% of the 802,000 patients with end-stage kidney disease (ESKD) in the US, and evidence in community-dwelling older adults suggests that vision impairment is a potentially modifiable risk factor for cognitive decline and dementia/Alzheimer’s disease (AD). Identifying and understanding modifiable risk factors for cognitive decline is a priority in geriatric nephrology: 87% of ESKD patients have abnormal cognitive function, resulting in a 21-25% lifetime risk of dementia/AD that is 19-fold higher than age-matched community-dwelling adults. We seek to address 3 knowledge gaps surrounding vision impairment among patients living with ESKD: 1) prevalence, risk factors, and causes/reversibility of vision impairment; 2) cognitive and vision-related sequelae; and 3) vision screening and treatment barriers. First, the true prevalence of vision impairment in ESKD patients is unclear. Refractive errors are common in the general population and small studies suggest that 29-67% of ESKD patients have diabetic retinopathy and 32-80% cataracts. Vision impairment is reversible in 90% of the general population; however, in ESKD vision impairment may be due to retinal damage from vascular disease and diabetes that is unlikely to be reversed. Second, while there is strong evidence of an association between vision and cognitive impairment among community-dwelling older adults, this association is unclear among ESKD patients. Vision impairment directly alters brain structure and reduces cognitive stimulation, and indirectly impacts dementia risk by causing social isolation, depression, and physical inactivity, all of which are common in ESKD. It is likely that the high prevalence of vision impairment may contribute to incident dementia/AD and other vision-related sequelae. Third, eye disease is underdiagnosed and undertreated in ESKD. Vision impairment may be uncorrected given the high burden of hemodialysis and negative social determinants of health borne by ESKD patients. Identifying screening and treatment barriers will help inform interventions to correct vision impairment and ultimately improve the lives of patients living with ESKD. We will leverage the infrastructure of our ongoing intradialytic interventions trial to launch the Vision Impairment Screening in Hemodialysis (VIS-HD) prospective cohort (n=300). Using an efficient study design in which all research will be conducted at 16 dialysis centers, we will assess visual acuity and test for retinopathy during dialysis, then develop interventions to mitigate vision impairment. We seek: 1) To characterize vision impairment prevalence, risk factors, and causes; 2) To identify cognitive and vision- related sequelae of vision impairment; and 3) To identify barriers to correcting vision impairment and develop a multi-modal intervention to mitigate vision impairment. This project will set the groundwork for a subsequent multi-center randomized control trial to correct vision impairment. Our findings will have an immediate impact on the lives of the ~802,000 adults who live with ESKD. With this project, we seek to address a NIA priority: To develop interventions for treating, preventing, or mitigating the impact of age-related conditions.

NIH Research Projects · FY 2026 · 2025-01

Project summary Sensation leads to perception and guides behavior. Information about the external world is first received by our sensory organs, then preprocessed and reformatted by subcortical structures prior to reaching the cortex where a percept is potentially formed. In olfaction, information reaches the cortex after only two synapses. Despite the critical role of olfaction for animal behavior across phyla, we still have a limited understanding of the principles of information processing in this sensory system. In mammals, inhalation of odors induces broad patterns of spatiotemporal activity across an array of glomeruli in the olfactory bulb, which in turn evoke complex activation patterns in second order neurons, the Mitral and Tufted cells (MTCs). These cells are embedded in a local network of inhibitory neurons and transmit information to higher brain areas. The goal of this proposal is to characterize the transformation of odor responses from glomeruli to MTCs in awake animals, explore the mechanisms underlying this transformation, and reveal its significance for information processing. Our proposal capitalizes on recent technological advances that overcome experimental limitations that have hampered progress in the field. First, we have developed a method for 2-photon calcium imaging of glomeruli and MTCs using fast indicators to record neuronal activity with temporal resolution comparable to electrophysiological recordings. Second, we currently can record responses of both glomeruli and MTCs in the same animal to hundreds of odor stimuli presented over multiple sessions. And third, we have developed a method for identification and characterization of functional connectivity between glomeruli and MTCs, by combining 2-photon imaging of MTCs with optogenetic pattern stimulation of glomeruli. Using this approach, we will characterize the responses of MTCs that are functionally connected to defined glomeruli using a large battery of odor stimuli. This will allow us to analyze the relationship between the response tuning of identified MTCs and the responses of the large glomerular array. Next, we will gain insights into the mechanisms responsible for shaping MTCs responses by optogenetic probing individual connections between glomeruli and MTCs in the presence of odor stimuli. Finally, we will test the idea that the transformation from glomeruli to MTCs plays a role in concentration invariant odor recognition by analyzing both glomeruli and MTC response invariance to changes of odor concentrations. The proposed experiments will generate fundamentally new insights into the rules governing sensory transformations in the peripheral olfactory system and will provide powerful new tools for the study of olfactory function in mammals.

NIH Research Projects · FY 2026 · 2025-01

Abstract. PD-1 blockade has become first line therapy of most non-small cell lung cancer (NSCLC). However, given the variable effectiveness of immunotherapy in this disease there is a need to better understand factors that affect individual’s response to this therapy. The lung microbiota plays an important role in host immune responses affecting subject’s susceptibility to inflammatory airway diseases. We have demonstrated that lower airway microbiota is associated with Th17 phenotype in the lower airways. In lung cancer, we identified a dysbiotic signature in the lower airways called pneumotypeSPT that is associated with transcriptomic signatures associated with lung carcinogenesis. Our preliminary data shows that subject s with lower airway microbiota characterized as pneumotypeSPTmay have increased mortality and increased immune checkpoint inhibitedtone. While gut microbiota signatures are partially associated with PD-1 blockade response, the effects of the lower airway microbiota on the immune tone and PD-1 blockade susceptibility are not known. Thus, we hypothesize that lower airway dysbiosis (pneumotypeSPT) alters the host inflammatory phenotype in the tumor microenvironment affecting the response to PD-1 blockade. We will evaluate airway/stool microbial signatures associated subjects’ response to PD-1 blockade by longitudinal assessment of the progression free survival (Aim 1). In addition, we will perform longitudinal sampling of airways, stool, and blood to expand our mechanistic understanding of the dynamic changes in the microbiome and host immune response during PD-1 blockade treatment (Aim 2). Validation and extension of the assessment of the microbiome and host inflammatory profile will be accomplished by using complementary approaches ( microbiota: 16S rRNA gene and metatranscriptome sequencing; inflammation: airway brush transcriptome, polychromatic flow cytometry, and single cell RNA sequencing of T cells). In Aim 3 we will use a preclinical mouse model of lung cancer that will allow us to evaluate the effects of dysbiosis on the lower airway immune tone and PD-1 blockade susceptibility. Identification of microbial signatures that affect the response to this first line therapy will be key to a personalized therapeutic approach and will identify novel modifiable targets. During the R37 extension period we will build on the data geing generated in these three aims focusing on how microbes affect the metabolic microenvironment in the lower airways. The metabolites being affected by lower airway dysbiosis in the setting of advanced stage NSCLC likely play a key immunomodulatory role that affect s PD-1 blockade treatment response. Thus, in Aim 4, we will use the lower airway and plasma samples obtained under Aims 1 and 2 to test the hypothesis that lower airway dysbiosis in patients with NSCLC is associated with changes in the metabolic environment. To that end, we will use an untargeted LC-MS metabolomic approach. Then, in Aim 5 we will use the preclinical model of lung cancer done in Aim 3 to test for causality by evaluating the hypothesis that induced lower airway dysbiosis will remodel the tumor metabolic microenvironment decreasing the responses to PD-1 blockade.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Despite cancer being typically depicted as a genetic disease, aberrations in epigenetics and gene expression play a determinant role in transformation and response to therapies. Derailed from their developmental paths, malignant cells may arrest their differentiation fate and activate alternative programs. Aberrant chromatin plasticity gives a survival advantage by expanding the repertoire of epi-clones and allowing them to react to the immune system, environmental stress, or exogenous treatments. Investigating which genetic and epigenetic aberrations alter chromatin homeostasis and how they shape tumor heterogeneity is thus a critical challenge to designing effective targeted approaches and predicting disease risk. Our laboratory dedicated extensive efforts to trying to understand the non-genetic drivers of leukemia, focusing on epigenetic modifications, long non- coding RNAs, and the study of 3D chromatin architecture. We previously investigated changes in large 3D structures in T-cell acute lymphoblastic leukemia (T-ALL), including chromosomal compartments (A vs B) and topological associated domains (TADs). More recently, using H3K27ac HiChIP analysis of enhancer-promoter interactions in T-ALL, we mapped and characterized the biological role of 3D “hubs” as DNA elements that interact with multiple other loci. We hypothesized that hubs represent regulatory units responsible for the transcription of key genes, serving as 'headquarters' of cell identity during development but also coordinating the tumorigenic program and shaping therapy responses. What we propose in this application is to expand our analysis and provide a complete characterization of 3D hub interactions in both immature T cell malignancies (T-ALL) and mature T cell neoplasms (focusing on T cell lymphoma), creating a continuum that spans normal T cells, their progenitors and malignant counterparts at distinct stages of differentiation. Our work will highlight how nuclear topologies and related gene networks evolve during T-cell development or get rewired to promote malignancy, providing new candidates to target therapeutically and deriving associations with clinical outcomes. This is of particular interest for T cell lymphoma, an aggressive and heterogeneous disease that represents a clinical emergency, given the lack of robust targeted therapies or immunotherapies. By leveraging the mapping of 3D hubs at multiple levels, we expect to define better DNA elements that are rewired by transformation and contribute to tumor progression or response to drug treatment. In this grant, we propose to a) extensively map 3D hubs in primary PTCL human specimens, b) perform CRISPRi and CRISPRko screens to identify biologically important hubs, c) characterize hub heterogeneity at the single cell level, and d) target them using both genetic and pharmacological tools. These experiments will test the hypothesis that 3D DNA hubs are elements that control transformation, tumor progression, and response to drug treatment.

NIH Research Projects · FY 2026 · 2024-12

Abstract: Occurring after subarachnoid hemorrhage (SAH), delayed cerebral ischemia (DCI) is a major cause of morbidity and mortality. In aneurysmal SAH, DCI occurs in up to 30-50% of survivors. The consequences of DCI are severe, in part because it is often detected too late by conventional monitoring and imaging protocols, preventing timely intervention. Near-infrared (NIR) optical monitoring of relative cerebral blood flow (CBF) after SAH has been performed by diffuse correlation spectroscopy (DCS). DCS has shown the potential of optical CBF measurements, but remains limited to sampling the forehead with marginal brain specificity. Quantitative CBF measurements are further hampered by superficial tissue contamination. Our group recently advanced a new approach called interferometric diffuse optics (iDO). In separate implementations, this new approach has provided highly parallel detection (~300x more channels than conventional single channel DCS detection) and time-of-flight (TOF) information. Here we propose to further enhance and unify these advantages in a single implementation (detection scheme) that improves the measurement signal-to-noise ratio by 100x and channel number by 1000x relative to single channel DCS, while also providing time-of-flight information. This unique approach will improve the SNR of the autocorrelation, from which optical CBF is derived, by ten million-fold compared to DCS (if all channels are pooled). The same system will also provide time-of-flight information to account for variability in head geometry and superficial blood flow and provide quantitative optical CBF that can be compared across time, locations, and subjects. In this proposal, we will develop a 1064 nm iDO system that uses the new concept of coherence engineering to provide TOF information and reduce S-C separation, thus improving photon counts (Aim 1). We will benchmark this new system against existing technologies in our laboratory and validate its capabilities (Aim 2). Finally, we will deploy an iDO instrument in the neuro-intensive care unit (ICU) for observational monitoring of SAH patients across the head and test whether optical CBF can diagnose DCI (Aim 3). Beyond DCI, the interferometric technology delivered here can be applied in ischemic stroke, traumatic brain injury, and other neurological disorders.

NIH Research Projects · FY 2026 · 2024-12

Nationwide, a widening gap in neurologic health outcomes exists, with some populations suffering a disproportionate burden of neurologic disease and in some cases, even seven times greater mortality than other groups. Here we focus on the neurologic disorder, multiple sclerosis, the most common disabling central nervous system (CNS) disorder of young adulthood. We have designed a collaborative research project to work alongside all individuals with MS including those associated with Black, Hispanic, and poverty-impacted communities. We posit that childhood adversity experienced at the individual, family, and neighborhood levels significantly contributes to worse health, particularly among high-risk groups. Here, we have collaborated with communities of interest (persons with MS who come from specific high-risk groups), community engagement partners, and a highly multidisciplinary research team. Together, we are aligned to collaboratively develop and execute a comprehensive, culturally informed multicenter study of childhood adversity and MS health outcomes involving predominantly individuals who self-identify as members of high-risk groups with MS. This community-engaged proposal advances clinical readiness by creating culturally sensitive research instruments, meticulously analyzing the relationship between childhood adversity and MS outcomes, and understanding the environmental and social factors influencing quality of life in minority and poverty impacted people with MS. The insights gained will guide the development of tailored interventions to improve health outcomes for all individuals with MS and to ensure those living with MS have optimal health and quality of life. Identified modifiable targets will be rapidly scaled into a clinical trial across the U.S. Network of MS Centers.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT During nervous system development, tissues need to move and split to form neuronal cell clusters and layers. They use attractant gradients for guidance and cellular rearrangement for splitting. However, how attractant gradients are established and how tissues split in two is largely unclear. To address these questions, we use the posterior lateral line primordium migration in zebrafish as a model. The primordium is a group of about 140 cells that migrates along the body of the embryo and deposits 5–7 mechano-sensory organs called neuromasts from its back. It expresses the chemokine receptor Cxcr4 and follows a trail of the Cxcl12 chemokine. We have used this system to show that the primordium generates an Cxcl12 gradient across itself by sequestering Cxcl12 in its rear through the alternate Cxcl12 receptor Cxcr7, a chemokine scavenger receptor, and that the primordium couples actin flow to its substrate, the basement membrane, through integrins and exerts highest traction stresses (force per area) in its rear to push itself forward. In Aim 1, we will determine how the extracellular matrix and the migrating primordium together shape the distribution of Cxcl12a using an Cxcl12 signaling sensor and knock-in lines that we generated. In Aim 2, we will analyze the role of RhoA-mediated actomyosin contraction, cell-cell adhesion and cell- extracellular matrix adhesion in orchestrating the splitting off of neuromasts from the back of the primordium using cadherin-based tension sensors that we adopted to zebrafish and in vivo traction force microscopy that we recently developed. Our approach combines the optical accessibility of the zebrafish primordium with quantitative imaging, embryonic and genetic manipulations, and sensors for chemokine signaling, RhoA signaling, tension forces and traction stresses to provide a quantitative understanding of the physical, molecular and cellular mechanisms underlying tissue guidance and tissue splitting, two key aspects in assemblying the nervous system. We anticipate that our proposed studies will have two broad impacts on the field of nervous system development. First, they will provide a quantitative understanding of how attractant gradients are generated by migrating tissues. Second, they will unravel the mechanics of tissue splitting. These insights are key to understanding major biological and medical problems including defects in neuronal development and disease.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT KRAS-driven non-small cell lung cancer (NSCLC) remains one of the most aggressive and lethal solid tumors. Current NSCLC therapies, although promising, have low efficacy against KRAS-driven LUAD. Because KRAS mutant tumors are resistant to standard-of-care treatments, there is an urgent clinical need to identify both druggable tumor-intrinsic vulnerabilities and approaches to boost responses to standard-of-care therapies. The Integrated Stress Response (ISR) enables tumors to overcome growth limitations and therapeutical interventions. However, little is known about how ISR activation in tumor cells impacts the microenvironment (TME). In our preliminary studies, we found that loss of ATF4, a major arm of ISR, inhibits tumor growth in immunocompetent animals in a T cell-dependent manner, strongly suggesting that tumoral ISR promotes immune evasion via induction of immunosuppressive molecules. Indeed, using a CRISPR/Cas9 genetic screen targeting ISR-responsive genes, we identified Lipocalin 2 (LCN2), a small glycoprotein, as a potent immunomodulatory molecule that suppresses anti-tumor T cell responses. LCN2 is upregulated in many challenging tumor types and is associated with poor prognosis. LCN2 is distinct from checkpoint molecules that have been studied in that it is a secreted molecule rather than a surface receptor. Thus, we hypothesize that LCN2 offers a novel therapeutic opportunity that complements the current immune checkpoint blockade (ICB). Our preliminary studies revealed that LCN2 is associated with T-cell exclusion in patient samples as well as in mouse models. We have developed human synthetic antibodies against mouse and human LCN2, and these antibodies are efficacious in the inhibition of tumor growth and in increasing T-cell infiltration in mouse models. Based on these exciting data, we propose the following Aims to define the role of LCN2 in the TME and develop a therapeutic strategy in lung cancer: 1) Characterize the impact of LCN2 on the composition of the TME; 2) Develop novel biological therapeutics that interfere with LCN2 and assess their efficacy as monotherapy as well as in combination with ICB; and 3) Determine the mechanism of action of LCN2 by utilizing a combination of genetically engineered models and a panel of anti-LCN2 antibodies. These studies will establish the mechanism of action of LCN2 in the TME, its use as a potential marker of immune evasion, and novel therapies that neutralize LCN2 function that may help overcome ICB non-responsiveness in lung cancer and potentially other challenging cancer types.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT The importance of tissue resident macrophages for pathogen clearance and tissue homeostasis is beginning to emerge. However, our understanding of the multifaceted roles these macrophages play in mucosal tissues such as the lung remains incomplete. The lung is a very complex organ with specialized structures to allow for adequate gas exchange. The pulmonary microenvironment is unique and has a direct and important influence on the resident immune cells, especially macrophage populations. One of the most important function of macrophages is to regulate type 2 inflammatory pathways during helminth infections and allow for the resolution inflammation and tissue damage after the pathogen is cleared. The precise cellular and molecular mechanisms that macrophage populations utilize to accomplish these critical functions in vivo are not well understood. We recently reported the discovery of an interstitial subset of CD169+ lung-resident macrophages that are transcriptionally and developmentally distinct from alveolar macrophages (AMs). These CD169+ interstitial macrophages (IM) are primarily localized around the large airways in mice and humans and in close proximity to the nerves in the bronchovascular bundle. Our work has shown that these nerve- and airway-associated macrophages (NAMs) are tissue resident, and express high levels of immunoregulatory genes that are strongly associated with type 2 immune responses under steady-state and inflammatory conditions. Nevertheless, the role of NAMs in regulating type 2 immune responses is not well understood. Using the Nippostrongylus brasiliensis (Nb) model our preliminary data shows that NAMs are critical for mediating type 2 immune responses and tissue repair following infection. Furthermore, we have observed that NAMs in particular continue to increase in numbers long after Nb is cleared, which suggests this macrophage subset may exhibit epigenetic changes reflective of an important role in mediating trained immunity. Indeed, our studies show that as late as 6 weeks after Nb infection mice exhibit remarkable protection from subsequent respiratory viral infections. Thus, the overarching hypothesis to be tested in this proposal is that lung resident macrophage subsets, (in particular NAMs) carry out distinct functions, and their unique positioning and remarkable gene expression profile make them critically important for regulating type 2 immune responses and tissue homeostasis. Furthermore, in response to pathogens that trigger a robust type 2 immune response lung resident macrophages exhibit hallmarks of trained immunity that have important consequences for subsequent heterologous infections.

NIH Research Projects · FY 2026 · 2024-12

Project Abstract Genetic scans for neuropsychiatric disorders like schizophrenia have uncovered hundreds of risk loci, yet we lack both the tools and conceptual approaches to dissect mechanism at this scale. One of the most robust schizophrenia and bipolar association signals lies near a human-specific repeat expansion within intron 3 of CACNA1C gene. CACNA1C encodes the predominant L-type voltage-gated calcium channel expressed in human central nervous system neurons, and a single missense mutation is responsible for the monogenic disorder Timothy Syndrome whose presentation includes neuropsychiatric symptoms. Through careful analysis of long-read sequencing data from a broad set of populations, we have decoded the complex structure of the CACNA1C repeat and developed tools for its assessment in commonly available short-read sequence data. We propose to fine map key features of regulatory activity at the CACNA1C repeat using long-read methyltransferase accessibility profiling (Fiber-seq). We will also apply a complementary synthetic regulatory genomics approach, to systematically dissect features of repetitive DNA in terms of repeat structure, unit content, and length. Finally, we will extend this approach to other repeats at potentially relevant genes genome-wide and apply our existing genome engineering pipeline to functionally screen candidates in cultured cells. This work promises to unlock a previously intractable locus as a model for how transcriptional mis-regulation leads to psychiatric disease.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY/ABSTRACT Dendritic cells (DCs) are the key sentinel cells of the immune system that directly recognize pathogens and initiate adaptive T and B cell responses. In addition to their essential role in antimicrobial and antitumor immunity, DCs are thought to control immune homeostasis and promote tolerance. Conversely, aberrant antigen presentation and/or cytokine production by DCs have been implicated in nearly every autoimmune disease. However, the role and mechanism of the tolerogenic function of DCs are poorly understood. In particular, the control of the "switch" between the tolerogenic and immunogenic DC function and the molecular programs underlying these functions remain largely unknown. Our preliminary studies have identified a potential molecular regulator of tolerogenic DCs, whose deletion impairs DC function and leads to the loss of T cell tolerance. The proposed project will seek to pinpoint the DC subset responsible for this phenotype (Aim 1) and characterize its molecular basis, including aberrant cytokine production (Aim 2) and impaired signaling (Aim 3). Collectively, these studies would help delineate the molecular control of tolerogenic DCs and provide insights into the mechanisms of DC-mediated peripheral tolerance.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Inadequate medication access and adherence causes poor health in the aging Medicare population—issues which are particularly salient among disadvantaged populations. The 340B Drug Pricing Program is an expansive, federal safety net program that intends to improve medication access and health outcomes for disadvantaged patients. It entitles qualifying hospitals or clinics to large manufacturer discounts when they purchase and dispense infused, injected, or oral outpatient drugs. The intent is for 340B hospitals to use savings to increase drug access and invest in services to improve outcomes for disadvantaged patients; however, there are no direct incentives nor oversight criteria to ensure this occurs, and facilities are permitted to dispense 340B drugs to patients regardless of individual social or financial need. Moreover, the 340B Program’s financial structure incentivizes prescription of higher volumes and more expensive drugs. While this could result in improved guideline-concordant medication utilization and health outcomes, it could also lead to dispensing potentially inappropriate medications or higher priced drugs. Although most 340B hospitals report using Program savings for the intended purposes, there is limited objective evidence to substantiate these claims. Whereas prior 340B research focused on Part B (physician administered) drugs, recent changes make it critical to understand its impact on Part D (pharmacy dispensed) drugs. Recent FDA approvals of expensive Part D specialty drugs has resulted in Part D drugs becoming lucrative for 340B hospitals. 340B channels for dispensing Part D drugs have also multiplied. Hospitals could originally dispense 340B drugs through (and share savings with) one contracted pharmacy. This restriction was removed after 2010. Now, 340B hospitals may contract with an unlimited number of community pharmacies. This study will link multiple datasets with a 100% sample of Medicare Part D enrollees, and use quasiexperimental analytical methods to evaluate the: 1) impacts of 340B Program growth on volumes and characteristics of Medicare Part D medications overall and among disadvantaged subgroups; 2) impacts of 340B Program eligibility on guideline-concordant Medicare Part D medication initiation, adherence, and health outcomes for 8 diseases, overall and by disadvantaged subpopulation; and 3) whether specific hospital-level characteristics are associated with positive impacts of 340B Program eligibility on guideline-directed medication use, adherence, and clinical outcomes in Medicare. This project aligns with NIA’s emphasis on health care disparities and patient adherence to treatment to promote health. Amidst competing legislative proposals to either reform the 340B Program or protect the status quo, this study will provide large-scale objective evidence on both intended and unintended consequences for Part D medication use and health outcomes to inform and guide 340B Program policy reform decisions and advance health equity.

NIH Research Projects · FY 2026 · 2024-11

Project Summary/Abstract In schizophrenia (SCH), impairment in cognitive function, a core element of this illness, is observed prior to the onset of psychosis and has been tied to long-term outcomes. One suggested pathophysiologic mechanism for the cognitive deficits in SCH is disturbances in the ability of neurons to engage in synchronous oscillatory activity, a phenomenon thought to be essential for normal cognitive function. Increased cognitive load normally results in gamma range (30 – 100 Hz) oscillatory activity in the dorsolateral prefrontal cortex (DLPFC) but the generation of gamma activity is impaired in subjects with SCH. Gamma oscillatory activity is dependent on networks of fast- spiking, parvalbumin positive (PV+), GABA interneurons (IN) which synchronize pyramidal cell firing. Fast- spiking PV IN are highly energy dependent and, in turn, highly dependent on mitochondrial function. Given the energy requirements of the PV IN, abnormalities in brain energetics and/or mitochondrial function may play significant role in the cognitive symptoms of SCH. Given that the generation of gamma oscillatory activity relies on cellular energy production it is highly sensitive to disruptions in mitochondrial function. Mitochondria generate the majority of energy in the brain producing 95% of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OxPhos) via the electron transport chain (ETC). An impairment in mitochondrial function will result in reduced energy generation and a shift from OxPhos to the pathway of aerobic glycolysis (AG; lactate production in the presence of O2), with a resulting increase of lactate and reduction in pH. The first enzyme in the ETC, mitochondrial complex I (MC-I), is the rate limiting step in neuronal oxygen utilization. Dysfunction of MC-I in SCH is observed in post mortem studies as well as in peripheral blood cells. In vivo measures of brain OxPhos using phosphorus magnetic resonance spectroscopy (31P-MRS) provide direct measures of ATP, phosphocreatine (PCr) and inorganic phosphorus (Pi) and suggest a deficit of OxPhos in SCH, although no clear pattern has emerged. The current application seeks to examine in vivo brain energetics in SCH by utilizing [18F]BCPP-EF positron emission tomography (PET) to establish MC-I distribution and 31P-MRS to measure more detailed brain energetics (ATP, PCr, Pi). 10 medication-free individuals with SCH and 10 age and sex matched HC will participate in this study. [18F]BCPP-EF standardized uptake value ratio (SUVR-1) will be measured in both groups in the DLPFC. We will test whether lower DLPFC SUVR-1 in SCH will predict impairment on the Brief Assessment of Cognitive Function in Schizophrenia. In the same subjects, at the same time, PCr/ATP and Pi/ATP will be measured with 31P-MRS and correlated with [18F]BCPP-EF SUVR-1. The data from this application will provide a more comprehensive understanding of MC-I in SCH and its relationship to the shift in brain energetics to AG. These results will lay the groundwork for understanding whether mitochondrial OxPhos is impaired in SCH and exacerbates the cognitive impairments observed in this illness. The ultimate goal is that a deeper understanding of brain energetics in SCH will lead to the development of improved therapeutics.

NIH Research Projects · FY 2026 · 2024-11

The graded distribution of attractant cues guides migrating cells to their ultimate destination during embryogenesis, in immune system response, and when cancer cells metastasize. Despite the broad importance of cell migration, it remains poorly understood how stable extracellular attraction gradients are formed and maintained in vivo. The migration of the posterior lateral line primordium in zebrafish embryos is an excellent model to address this question because the primordium can be imaged at high spatial and temporal resolution and manipulated genetically with spatial and temporal control. The primordium expresses the Cxcl12a (Sdf1a) chemokine receptor Cxcr4b and migrates along a stripe of uniform Cxcl12a expressing cells. As the primordium migrates, it generates a linear signaling gradient across itself. The formation of a linear gradient requires the presence of a local source and a local sink. The Cxcl12 clearance receptor, Ackr3b (Cxcr7b), is expressed only in the back of the primordium and serves as a local sink. However, the Cxcl12a expression stripe does not constitute a local source. Therefore, it is unclear how the primordium generates a linear Cxcl12a gradient. One possibility is that Cxcl12a is normally sequestered by the extracellular matrix and that the migrating primordium employs a mechanism to locally liberate Cxcl12a to create a local attractant source. Indeed, my preliminary investigation suggests that the extracellular matrix negatively regulates Cxcl12a availability and that Cxcl12a binding to proteoglycan GAG chains is required for proper migration. In this project, I will determine whether Cxcl12a binding to GAGs is required for the formation of a linear Cxcl12a gradient (Aim 1) and whether heparan sulfate proteoglycans are required to tether Cxcl12a along the migratory route (Aim 2). Finally, I will investigate the mechanism by which the primordium releases bound Cxcl12a to generate a local source (Aim 3). To complete this project and prepare myself for a career as an independent investigator, I have created a training plan to develop expertise in genetics and quantitative imaging. My choice of mentor, collaborators, laboratory and institution ensures I have the resources and support necessary to perform the work described here and to receive meaningful feedback from developmental geneticists and microscopy experts throughout the project.

NIH Research Projects · FY 2026 · 2024-11

Abstract The human intestine retains countless microbes, existing in a mutualistic relationship with the host by providing nutrients and other metabolites necessary for overall well-being. Developing tolerance or inflammation to the countless commensal microbes within the gut is dependent on antigen presenting cells (APCs) and their interactions with naïve T cells. Thus, understanding how heterogeneous populations of APCs modulate immune responses within the gut in response to gut microbiota provides potential avenues to developing strategies to mitigate inflammatory diseases of the intestine such as inflammatory bowel disease (IBD) while also adding to our understanding of commensal immunity. The goal of this project is to investigate a newly discovered, distinct antigen presenting cell expressing RORgt, a nuclear transcription factor not classically associated with antigen presentation, within the gut. This RORgt+ APC has been shown by our group and others to be required for the generation of gut microbe-specific induced Tregs (pTregs), thereby maintaining intestinal homeostasis. However, while there is consensus in the field regarding the existence of a new RORgt+ APC required for the generation of pTregs to microflora, there is great debate as to the definitive identity and behavior of this population. Various groups have proposed different candidates of RORgt-expressing APCs as the essential population coordinating peripheral Treg responses to gut microbiota. This project aims to not only shed light on the blurred lines among the various subsets of RORgt-expressing APCs, but also to examine the nature of these cells, specifically where these APCs reside in the gut, what their behavior is within the intestinal microenvironment, and which cell types they interact with, both in homeostatic and pathogenic conditions. These objectives will be addressed by using a combination of intricate transgenic mouse manipulation, deep multi-omic analysis of fate-mapped RORgt+ APCs in different tissues and perturbations, and advanced microscopy techniques, including high-resolution multiplexed, volumetric imaging and intravital microscopy. This research will further our understanding of the mechanisms by which tolerance is established towards the expansive microbial ecology residing within the gut. Through these results, targeted therapies can be developed to promote commensal tolerance within the gut and alleviate inflammatory symptoms commonly observed in autoimmune disorders such as inflammatory bowel disease.