Johns Hopkins University

NIH Research Projects · FY 2026 · 2024-06

Project Summary/Abstract Prospectively selecting an appropriate sequence of actions from a large number of alternatives requires extensive computation. Although behavioral and modeling studies have advanced our understanding of how the internal model of the animal’s environment might be interrogated to evaluate the outcomes of future actions, the biological mechanisms of such computation remain poorly understood. In addition, new techniques to monitor the activity of many neurons in multiple brain areas are enabling researchers to systematically test theories of how temporally extended computations for high-order cognition like planning might be subserved by broadly distributed neural activity. To capture these exciting opportunities, we have chosen to study the neural basis of planning during the four-in-a-row task, which is both rich enough to keep the essential elements of complex planning and tractable for rigorous computational and neurophysiological investigations. The objective of the four-in-a row task is to place four consecutive stones in a grid before the opponent does so. This task allows us to study the neural processes for iteratively evaluating possible outcomes or values of alternative action sequences across many well-defined states. Recent work has characterized the computational strategies of humans in this task and how they are refined during practice. In addition, our preliminary studies show that non-human primates can be trained to perform the same task. In Aim 1, we will apply rigorous statistical and machine learning techniques to understand how the animals use feature-based evaluation and potentially tree search to make a move. In Aims 2 and 3, we will examine how computational aspects of planning rely on the coordination between neural populations in fronto-striatal and fronto-hippocampal networks. In Aim 2, we will simultaneously record the activity of many neurons in the dorsolateral and dorsomedial prefrontal cortex and in the caudate nucleus to test how these regions are involved in integrating various task features during action selection. In Aim 3, we will simultaneously record from the prefrontal cortex and hippocampus to test whether dynamic changes in the state representation in the HPC are reflected by successive transformation of neural signals related to values and actions in the PFC. We will also test whether sequential moves decoded from neural activity in the HPFC and PFC during replays correspond to past and future choices made by the animal. The results from these experiments will improve our understanding of how the brain develops good plans adaptively.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Infections with the parasitic nematode Ascaris lumbricoides affect up to an estimated 1.2 billion people worldwide, causing significant disease and accounting for the loss of 749,000 Disability Adjusted Life Years (DALYs) annually. Treatment of these infections in most endemic regions depends on mass drug administration (MDA) programs primarily comprising benzimidazoles (BZ), such as albendazole and mebendazole. Large-scale and prolonged usage of BZs selects for resistance in parasitic nematodes, as observed in veterinary parasites (e.g., Haemonchus contortus, a parasite of small ruminants). Although no confirmed cases of BZ resistance in human ascariasis have been described, BZ resistance has been confirmed in ascarids of veterinary importance. Importantly, these veterinary parasites also appear to lack canonical alleles associated with BZ resistance in other parasite species, suggesting that resistance mechanisms in ascarids likely differ. Everything currently known about BZ resistance comes from studies of the model nematode Caenorhabditis elegans and closely related parasites such as H. contortus. However, 350 million years of evolution separate C. elegans and ascarids, limiting its use as a model for ascarid research. Therefore, it is necessary to establish a new, more closely related, model to study BZ resistance in ascarids. Ascaridia dissimilis offers a powerful model system to study BZ resistance in human ascarids because established resistant and susceptible isolates exist, labor costs are lower than other veterinary parasites, and importantly no human infections are required. Human parasites cannot be readily studied because of the ethical issues associated with controlled infections, as well as difficulties in manipulating such a model. This project will identify genetic variants associated with BZ resistance in ascarids, using poultry ascarids as a new model system, allowing for diagnostics to be developed and improving treatment programs to control human infections. Aim 1 will create high-quality reference genomes for sensitive and resistant A. dissimilis isolates. Reference genomes will allow known resistance associated genes to be analyzed for high-impact variants, and enable future studies, including genome-wide mapping. Aim 2 will use genetic crosses and BZ selection to create recombinant isolates with BZ resistance associated loci in an otherwise susceptible background. After initial crossing of the resistant and susceptible isolates, progeny will be backcrossed with the susceptible parental line and selected for BZ resistance and used in a bulk-segregant analysis approach to identify BZ resistance loci. This innovative poultry ascarid system enables discoveries of conserved BZ resistance loci in a tractable model. Results can then be translated to human ascarids to improve the quality of care and quality of life for infected individuals across the developing world.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Mounting evidence suggests that magnetic fields may modulate important functions in cells. For example, magnetic fields can influence the spin state of photo-generated radical pairs in many flavoproteins, determining the rate of downstream reactions that govern cellular behaviors including circadian rhythms, DNA repair, and navigation of migratory birds. However, only low-to-moderate efficacy has been reported in clinical applications such as transcranial magnetic stimulation (TMS) and magnetotherapy, to treat epilepsy, depression and chronic pain. Improvement in treatment efficacy has been long stalled because the underlying molecular mechanism is poorly understood. This lack of progress is mostly due to not knowing the molecular mechanism of magnetic modulation. To measure the effective intracellular magnetic field to which biomolecules are exposed is the first step of building such understanding. The intracellular magnetic field is likely heterogeneous and not equivalent to the externally applied field of TMS or magnetotherapy, due to heterogeneous cellular compositions with varying magnetic permeabilities, as well as the heterogenous dynamic magnetic fields resulting from ion fluxes through ion channels. Currently no appropriate magnetometer exists to map the heterogeneous intracellular magnetic fields, though cellular measurement has been attempted using nitrogen a vacancy-center nanodiamond-based magnetometer, which can only provide sparse spatial readouts across the cell. Moreover, the necessity of subjecting cells to microwave radiation during nitrogen vacancy-center nanodiamond-based magnetometry is potentially harmful to cells. Herein we propose a genetically encoded magnetometer (GEM). GEM is a recombinant protein the backbone of which is a modified version of magnetosensitive flavoprotein. We will demonstrate that the heterogenous intracellular magnetic field can be mapped by expressing GEM in cells at unprecedented spatial resolution without the use of microwaves. If successful, GEM will enable the mechanistic study of TMS and magnetotherapy. In addition, it may also aid the evaluation of biological impacts due to pervasive presence of devices emitting electromagnetic waves.

NIH Research Projects · FY 2025 · 2024-06

Abstract Three million people worldwide are exposed to organophosphates (OP), most of whom will survive with long term side effects. These side effects include cognitive problems, mood disorders, and other neurological issues. These side effects have underlaying molecular mechanisms which have yet to be uncovered. This knowledge gap is a direct result of a lack of research tools available, however, two new tools have recently become available to close this knowledge gap. The first is a novel mouse model, termed the KIKO mouse, which contains two key genetic modifications: 1. knock out of the OP-binding serum carboxylesterase and 2. knock in of the human acetylcholine esterase. These modifications produce a vastly improved rodent model of OP intoxication. The other is matrix assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI). MALDI MSI combines the power of mass spectrometry with spatial resolution. Briefly, discrete mass spectrometry experiments are generated across a fresh-frozen tissue section to generate ion density maps of metabolites, neurotransmitters, lipids, and N-glycans. These two novel and powerful tools will allow for unprecedented molecular information on the short- and long-term effects of OP intoxication. We hypothesize that OP intoxication generates significant molecular changes in neurotransmitters, metabolites, lipids, and N-glycans. Our preliminary data shows significant differences in metabolites, neurotransmitters, and lipid oxidation in KIKO mice fifteen minutes post-exposure. Literature data supports changes in N-glycans associated with neuroinflammation. To test this hypothesis, in Aims 1 and 2, we will expose KIKO mice to 1xLD50 of sarin followed by the currently fielded countermeasure 2-PAM and atropine. Control animals will be given an equivalent volume of water for both exposure and treatment. Animals will be euthanized at 24 hours, 3-, 6-, and 12-weeks post exposure for analysis of metabolites, neurotransmitters, lipids, and N-glycans from brain, spinal cord, and blood. In Aim 3 we will expose pregnant KIKO mice to 1xLD50 of sarin followed by the currently fielded countermeasure. Dames will be allowed to continue their pregnancy and the offspring will be euthanized at early adult (8 weeks), mature adult (14 to 16 weeks), mid-life (40 weeks) and geriatric (78 weeks) of age for analysis by MALDI MSI. Brains, spines, and blood will be collected for analysis of metabolites, neurotransmitters, lipids, and N-glycans. From these data we will generate novel targets in the treatment of OP intoxication and its long term side effects.

NIH Research Projects · FY 2025 · 2024-06

NSF Awards · FY 2024 · 2024-06

The vast wind-energy potential above deep ocean waters has motivated serious consideration of floating wind farms. While promising, improvements to system reliability and lower costs are imperative for floating wind farms to begin playing a significant role in the transition to renewable energy sources. Key elements to enable both improved reliability and cost reductions include improved understanding of the complex fluid dynamical interactions between different types of ocean waves, turbulent winds in the marine atmospheric boundary layer, and multiple wind turbine wakes in floating wind farms as well as tools for their prediction. This project will develop and apply novel, accurate, and practical computational and experimental tools to probe these complex fluid dynamical interactions. It will fill knowledge and technology gaps in our ability to predict complex interactions between floating turbine wakes, prevailing winds, and wave fields. The project will help educate graduate students and include outreach activities with the Johns Hopkins Center for Educational Outreach to engage with local K-12 schools in Baltimore and the Oregon Science and Industry Museum in Portland to perform demonstrations of findings to a broader audience through their science communication program. The main goals of this project are to: (i) Develop improved and practically applicable surface flux parameterizations required for Large Eddy Simulations of the marine boundary layer above ocean waves. The novel computational framework uses simple non-deforming coarse meshes including a phase-resolving model with computational costs similar to traditional equilibrium wall models that cannot resolve wave phase-dependent phenomena. This approach is generally applicable to any non-breaking wavefield, from monochromatic to multi-frequency/omni-directional ocean-waves characterized by broad spectra. (ii) Improve experiment scaling concepts to better adapt laboratory-scale experiments to accurately reproduce relevant physics of field-scale floating wind farms and to generate pertinent experimental datasets to compare with models. Scaling is based on several newly defined dimensionless ratios involving turbine/platform inertia and flow-dependent parameters. Scaled laboratory experiments will simultaneously capture the turbulent wind velocity field, wave kinematics, and model wind turbine motion and generated power. (iii) Generate high quality experimental datasets under controlled conditions in wind-tunnel/wave tank laboratory experiments to test and validate the new LES wall modeling approaches under conditions of increasing complexity, elucidate conditions under which wind-wave-turbine interactions can increase or decrease power production, wake recovery, and unsteady structural loading strength, and finally, apply the improved computational and laboratory modeling tools to offshore conditions based on field data obtained along the US West Coast (relevant to floating wind energy applications). The outcome will be improved characterizations of floating turbine response such as unsteady loading as function of various wind and sea-states. The project was funded by the NSF ENG Fluid Dynamics program and the DoE/EERE Wind Energy Technology Office. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-06

ALPHA- EMITTER THERAPY OF OSTEOSARCOMA PROJECT SUMMARY Three-year overall survival for patients with recurrent osteosarcoma (OS) is 20%. Current therapy for metastatic osteosarcoma (OS) is largely ineffective. Over the past four decades no new therapies have been identified for OS. Our overall objective is to evaluate the potential efficacy and toxicity of targeted alpha-particle radiopharmaceutical therapy (αRPT) against OS. Targeted alpha-emitter therapy is a promising treatment modality that is not susceptible to the resistance mechanism observed for chemotherapy, traditional radiotherapy, targeted (i.e., pathway inhibition) therapy and immunotherapy. This is because alpha-particles cause massive and irreparable DNA double-strand break damage, irrespective of oxygenation, dose-rate, cell signaling or mutational burden. Osteosarcoma expresses the ganglioside GD2 receptor that can be targeted by the anti-GD2 antibody (Ab), Hu3F8. We propose to evaluate the safety and efficacy of 225Ac-Hu3F8 (A3F8) in a naturally occurring, large animal model of osteosarcoma. Actinium-225 emits 4 alpha-particles per decay and has a 10-day half-life. These experiments in client-owned dogs, which develop metastatic OS disease at a higher rate than people, would be the first evaluation of radiopharmaceutical therapy (RPT) with an alpha-emitter- conjugated Ab that targets both soft-tissue and calcified disseminated OS — a highly radioresistant disease. A two-cycle treatment scheme will be used wherein a fixed administered activity (AA) of A3F8, will be directly imaged by SPECT using a novel proprietary technique developed by Rapid, LLC (a Hopkins startup that has licensed α-particle emitter dosimetry and imaging technology) to obtain pharmacokinetics (PK) for dosimetry and treatment planning to identify the AA that balances potential toxicity with maximum anti-tumor efficacy. The specific aims are: 1. Identify the maximum tolerated absorbed dose (MTAD) to the red marrow in client-owned dogs with OS; utilizing SPECT imaging, collect PK to relate dose-limiting organ (DLO) absorbed dose (AD) to measured toxicity. 2. Determine treatment efficacy at the MTAD. 3. Evaluate how different measured or calculated quantities (e.g., tumor burden, tumor AD and DLO AD) are related to toxicity and efficacy. 4. Using data collected in Aims 1-3, develop a pharmacokinetic/dosimetry model that will help guide optimization of αRPT treatment in human OS patients. New treatments that are fundamentally different from those currently available are urgently needed for osteosarcoma. Radiopharmaceutical therapy with the highly potent alpha-emitter, 225Ac, is such a therapy. The proposed studies would yield required data to launch a clinical αRPT trial against OS in humans.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY/ABSTRACT The blood brain barrier (BBB), formed by vascular endothelial and supporting cells, functions to regulate blood- brain exchange of substances and cells, and to protect the central nervous system (CNS) from neurotoxins and pathogens. Building on our efforts toward ameliorating HIV-associated CNS complications and achieving HIV cure, we now must address the growing evidence that BBB impairment is associated with acute and/or repeated cocaine use . Cocaine misuse (intranasal, intravenous, inhalation) is common among people living with HIV (PLWH) and viral reservoirs in brain can be seeded by infected immune cells that penetrate the BBB . As the field pursues new strategies to mitigate CNS consequences of HIV infection in the context of substance use, and achieve cure, it will be critical to define the mechanisms by which HIV-infected cells and cocaine impact BBB integrity and the subsequent consequences on both the viral reservoir and cognition in PLWH. We propose a central model wherein historical cocaine misuse causes a persistent deficit in BBB integrity that underlies cognitive impairment in PLWH. In this model, PLWH with historical cocaine use disorder (CUDH) 1) have higher prevalence of CCR2+ALCAM+ intermediate monocytes that harbor HIV proviral DNA and migrate to the brain, and 2) this higher prevalence of CCR2+ALCAM+ intermediate monocytes results in increased transmigration across the BBB disrupting BBB permeability and tight junctions (TJ). In vivo studies in humans have not assessed CUDH and long-term BBB integrity in PLWH. The recent development of the Water-extraction-with-phase- contrast-arterial-spin-tagging (WEPCAST) MRI sequence facilitates in vivo measurement of BBB permeability to small molecules without contrast. We propose using WEPCAST MRI to assess BBB integrity in vivo in 175 PLWH with CUDH and 75 PLWH without CUDH. We will determine the effect of immune cell phenotypes, HIV proviral DNA burden and in vitro alterations to BBB TJ on in vivo BBB integrity in PLWH with and without CUDH. Aim 1: Determine the contribution of immune cell phenotypes to BBB permeability in PLWH with and without CUDH. We will assess BBB permeability via WEPCAST in relation to monocyte and T cell phenotypes implicated in transmigration of activated cells across the BBB. Aim 2: Determine the contribution of immune cells harboring HIV proviral DNA to BBB permeability in PLWH with and without CUDH. We will assess HIV proviral DNA via the Intact proviral DNA assay (IPDA) in monocytes and CD4 T cells in relation to BBB permeability via WEPCAST. Aim 3: Determine mechanisms by which monocytes that harbor HIV proviral DNA increase BBB permeability in PLWH with CUDH. We will assess BBB permeability using an in vitro model of the BBB to elucidate how HIV infected monocytes shape BBB tight junctions. Our in vivo study utilizing a noninvasive BBB integrity measure combined with immunophenotyping, reservoir analysis and a mechanistic approach to determine the effect on BBB TJ are highly innovative. Data will provide support for addressing BBB integrity in PLWH with CUDH and guide investigation of therapeutics aimed to promote BBB health in substance use disorders.

NIH Research Projects · FY 2026 · 2024-06

PROJECT ABSTRACT Hepatocellular carcinoma (HCC) is a significant global health problem and is expected to become the third leading cause of cancer mortality in the United States (US). Among patients with early-stage HCC, approximately 70-80% of patients experience disease recurrence after surgical resection, and no systemic therapy is currently approved in the perioperative setting. Neoadjuvant immunotherapy (immunotherapy administered prior to a potentially curative HCC resection) aims to utilize the primary tumor as a source of antigens to enhance systemic anti-tumor immunity and prevent disease recurrence. Neoadjuvant studies also offer an opportunity to interrogate the mechanisms behind both tumor sensitivity and resistance to therapies by providing larger quantities of tumor to enable in-depth profiling of the tumor immune microenvironment (TiME) that is not possible with needle biopsies. We are conducting a neoadjuvant platform study to evaluate multiple programmed cell death protein- 1 (PD1)-based combinations in HCC. The three study arms are nivolumab (NIVO, anti-PD1), NIVO plus cabozantinib (CABO, a multi-kinase inhibitor of VEGFR-2, AXL, and c-MET), and NIVO plus relatlimab (RELA, anti-Lymphocyte Activating 3, LAG3). Our overarching hypothesis is that the addition of CABO and RELA to anti- PD1 will bypass barriers to recruitment and function of T cells in early-stage HCC. We will also investigate tertiary lymphoid structures (TLS) as a conserved mechanism of response to neoadjuvant anti-PD1-based immunotherapy, based on our preliminary data showing a strong association between the formation of TLS and major pathologic response in HCCs treated with anti-PD1 immunotherapy. In Aim 1, we will utilize high-parameter multiplex imaging mass cytometry (IMC) on pre-treatment and post-treatment surgical resection specimens to determine the additive effects of CABO and RELA on the density and spatial relationships of immune cells within the TiME. We will also evaluate whether the triple combination of CABO, anti-PD1, and anti-LAG3 enhances T effector (Teff) recruitment, function, and survival in preclinical models of HCC. In Aim 2, we will investigate the clonal dynamics of TLS that arise within anti-PD1 treated HCCs through T-cell receptor (TCR) and B-cell receptor (BCR) sequencing of individual lymphoid aggregates. We will determine the immunophenotype of TLS through spatial and functional analysis of TLS-associated T cells and B cells. In Aim 3, we will determine the cellular composition and organization of immunotherapy-associated TLS in three-dimensions by employing a new technology (CODA) that renders 3D reconstruction of 2D image stacks. This aim will provide the first multicellular structure-function analysis of TLS in immunotherapy-responsive HCC to understand if TLS are highly conserved within tumors and across tumors. The final deliverable for this project is understanding the mechanisms of response to promising anti-PD1 combinations, and the identification of effective and feasible therapeutic combinations in the neoadjuvant setting for HCC that can be brought forward in larger studies to ultimately improve outcomes for patients with early-stage HCC.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Stereotactic Body Radiotherapy (SBRT) has been established as an effective, safe, and feasible first-line option in lung cancer. The quest for dose escalation to increase tumor control and survival benefit, and simultaneously to minimize normal tissue complication, requires precise radiation delivery to a region including the cancerous target and the smallest possible ring region around the target (called margin) to ensure sufficient dose to the target in the presence of positioning uncertainty, mainly caused by respiratory motion. This is especially critical for SBRT, as it is vulnerable to geometry errors due to high dose per fraction, a steep dose gradient, and the long delivery time that increases chances of changes in motion. Pre-treatment imaging technologies have been used to aid the position of tumor against the treatment beam. Yet, a margin size of 6- 10 mm is still routinely used to accommodate systematic and random changes in respiratory motion magnitude, baseline, and period. Consequently, high dose (close to prescription level) is delivered to a large volume of normal tissue, yielding toxicity concern. There is a strong, but unmet need for margin reduction in lung SBRT. The ultimate form of margin reduction is 4D radiotherapy (RT) that modifies multi-leaf collimator positions in real time in response to tumor motion to always direct radiation to the tumor. Knowing tumor position in real time is the prerequisite for 4D RT. Nonetheless, to date, no approach can provide accurate and reliable 3D tumor tracking. To address this problem, our group proposed in 2016 a tumor tracking scheme by measuring scattered x-ray photons and lately demonstrated its potential feasibility using state-of-the-art photon counting detection technology. The overall goal of this proposal is to develop and translate a prototype system with appropriate capability for 3D tumor tracking, to evaluate its performance in phantom and patient studies, and to demonstrate its clinical impacts, by jointing the strong and complementary expertise of teams at Johns Hopkins University, Massachusetts General Hospital, and Varex Imaging. We will pursue four specific aims (SAs). SA1. Develop a prototype hardware system to image tumor region with scattered kV photons. SA2. Develop a software system for data processing pipeline and tumor tracking. SA3. Integrate the developed systems to form a prototype and perform phantom experiments to characterize its performance. SA4. Implement the system in clinic, perform patient studies to demonstrate feasibility and advantages of real-time 3D tumor tracking, and translate it to end users. The innovation of this project is a novel system measuring scattered kV x-ray photons to image tumor regions and using it to track tumor motion. Deliverability is ensured by preliminary studies and the team with complementary expertise. Our project will overcome a major hurdle in 4D RT, enabling margin reduction in lung cancer SBRT and hence generate substantial clinical impacts. Although focusing on lung cancer SBRT, the technology is expected to be translatable to many other tumor sites facing the same need for real-time tumor tracking.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY / ABSTRACT This proposal aims to improve our diagnosis and mechanistic understanding of right ventricular (RV) myocyte dysfunction in heart failure patients with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). Our inability to accurately identify RV failure worsens prognostic and therapeutic efforts in many HFrEF-PH clinical scenarios. RV myocyte contractile reserve indices, such as calcium-activated isometric tension and length-dependent active tension, are reduced in end-stage human HFrEF-PH RV. The latter, a key contributor to chamber Frank-Starling reserve, is severely depressed in HFrEF-PH yet entirely uncaptured by clinical indices. This deficiency highlights one potential reason why clinical tools fall short. A shortcoming of this work was its study of end-stage disease; correlates of myocyte dysfunction from earlier-stage disease would provide more clinically useful insight. Our central hypothesis is that clinical identification of RV myocyte disease in HFrEF-PH requires measuring RV contractile reserve during exercise. Our prior study of primary PH patients supports this, and new data in patients with PH secondary to heart failure do so as well. We also reveal a novel mechanism linking poor recruitment of super-relaxed myosin to poor myocyte length-dependent tension. This links, for the first time in humans, thick filament myosin to RV myocyte and chamber reserve. Dissecting these findings will clarify mechanism and help guide the use of novel direct-acting sarcomere drugs for such myocyte deficits. We will test our hypothesis via three Specific Aims. In Aim 1, we test whether RV exercise reserve measures are better than resting RV measures at identifying RV myocyte contractile dysfunction. We will do this by prospectively measuring rest and exercise RV function using clinical and pressure-volume loop-derived RV indices and comparing their ability to identify intrinsic RV myocyte contractile failure, the latter ascertained from concurrently obtained RV biopsies. In Aim 2, we test whether hypophosphorylation of protein kinase A- protein targets or hyperphosphorylation of sarcomere Z-disc scaffolding proteins blunts length-dependent activation in HFrEF-PH RV myocytes. We will assess myocytes under the influence of select kinases and phosphatases, assess thick filament super-relaxed myosin recruitment, and test the effect of specific modifications on length-dependent force in human engineered heart tissue. In Aim 3, we test the ability of novel direct-acting sarcomere drugs, termed myotropes, on ex vivo HFrEF RV myocyte length-dependent tension. We also test whether newfound Aim 1 clinical measures identify patients with better drug response. Through this proposal, we expect to deliver novel clinical indicators of intrinsic HFrEF-PH RV myocyte failure. By coupling these clinical indicators to biophysical mechanisms and drug responses, we hope to usher in novel treatments for RV failure. These goals, which align with those of the NHLBI, would fulfill a major unmet need for RV failure due to HFrEF-PH. The PI Dr. Hsu, an early-stage investigator, has developed the necessary clinical-translational expertise and has assembled an exceptional scientific team to deliver on this proposal.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY Staphylococcus aureus is a common cause of bacterial infections in the United States (US), including skin and soft tissue infections and invasive infections (e.g., sepsis, pneumonia and necrotizing fasciitis). Carriage of S. aureus is an established risk factor for infection. Despite observed carriage prevalence similar to that in the general United States population, Indigenous populations experience a disproportionate burden of S. aureus disease, largely due to disparities in the social determinants of health. Decolonization can be achieved using a variety of regimens, each of which has requirements that could be challenging in under-resourced settings. In addition, people are often re-colonized after one-time decolonization and recurrent infections are common. Existing strategies have not been sufficient to control disease and a better understanding of the epidemiology of S. aureus carriage is needed so that effective and feasible approaches to decolonization can be developed. This proposal builds on a long-standing partnership between the Johns Hopkins Center for Indigenous Health, the White Mountain Apache Tribe and the Indian Health Service to produce infectious disease and behavior change interventions that have been scaled across Indigenous populations and the world. We are currently evaluating a community-informed and novel approach to achieve long-term carriage suppression using a combined education and sustained biomedical intervention in the W hite Mountain Apache community in work funded through the Native American Research Centers for Health Program. In this proposal, we will expand this work to answer key outstanding questions about S. aureus epidemiology. Within the context of the trial, we will: 1) evaluate S. aureus genomic diversity within households at the baseline visit by characterizing stored samples collected from individuals, indoor pets, and surfaces within households; 2) evaluate S. aureus transmission dynamics and reservoirs of carriage within households by recruiting and following a subset of households in the trial for four months and testing samples collected from individuals, indoor pets, and surfaces at each visit; and 3) assess reacquisition of S. aureus among individuals receiving a carriage suppression regimen in the trial by characterizing stored samples from each visit. This work will generate critical preliminary data that will inform the design and evaluation of decolonization interventions to be implemented in similarly under-resourced and burdened communities.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY Infectious disease is a major threat to human health worldwide. The emergence of antibiotic resistance pathogens necessitates the development of new drugs to treat infections. A fundamental challenge in developing antibiotics is that many pathogens replicate inside host cells rendering them inaccessible to antimicrobial agents. The critical processes that govern pathogen growth within host cells represent promising new targets for therapeutic intervention. Pathogens encounter a broad assortment of challenges within the host. The ability to perceive and adapt to these challenges is a critical determinant of virulence. These adaptations are mediated by sensory systems that detect host-imposed insult or alterations in their local environment and drive an appropriate response. Many bacterial pathogens that grow inside host cells do so in specialized compartments called replication vacuoles. Maintaining the integrity of the replication vacuole is paramount to bacterial survival and growth as it provides protection against host surveillance systems that detect and eliminate pathogens. Disrupting this process would thus limit bacterial burden and enable pathogen killing by the host. Despite vacuole integrity being paramount for pathogenesis, the mechanisms responsible and how bacteria sense and respond to defects in this process are poorly understood. We have identified a cell-surface signaling system employed by the bacterial pathogen Legionella that plays a central role in promoting vacuole integrity. Legionella is the causative agent of a life-threatening pneumonia called Legionnaire’s disease and a world-wide health problem. The goal of this research is to characterize how signals are propagated and the response pathway that compensates ensures vacuole stability. This work will define an unprecedented molecular surveillance system employed by a vacuolar pathogen to sustain its replication compartment and thus, a new paradigm in microbial pathogenesis. As vacuole integrity plays is a central role in defining the virulence of numerous intracellular pathogens, this work will have broad implications across the field of microbial pathogenesis. This work will provide unprecedented insight into a critical event that determines the outcome of an infection and a means to develop new strategies to treat disease.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY G-protein coupled receptors (GPCRs) are seven transmembrane domain receptors that make up the largest class of proteins in the mammalian genome. When activated by an appropriate ligand, these receptors elicit specific and coordinated cellular responses that dictate a wide variety of physiological processes. One such receptor that I have begun to investigate is GPR39. While initial studies reported that zinc is the endogenous ligand, more recent reports demonstrated that zinc acts as an allosteric potentiator of GPR39 signaling. Although the endogenous ligand for GPR39 is still unclear, synthetic ligands have been key in understanding GPR39 signaling and have implicated functions for GPR39 in the heart, bone, skin, pancreas, and gastrointestinal tract. However, despite its well-recorded abundance in the kidney, there have been no published studies into its role in renal physiology. In preliminary data, I find that GPR39 localizes to principal cells (AQP2-positive) in the inner medullary collecting duct, and data from our collaborators indicates that GPR39 activation influences renal water handling. I therefore hypothesize that GPR39 activation inhibits water reabsorption by sequestering AQP2 in sub-cellular compartments. In agreement with this hypothesis, I find that treatment of collecting duct cells in vitro with a GPR39-specific agonist, cpd1324, altered dDAVP-induced AQP2 localization. Here, I propose two Specific Aims to uncover the mechanistic role that GPR39 plays in renal water handling. In Aim 1, I will examine three potential mechanisms by which GPR39 activation influences AQP2 trafficking in vitro. Aim 1A will test whether GPR39 activation inhibits AVPR2 expression and activity, and Aims 1B/C will test whether GPR39 activation inhibits forward trafficking (Aim 1B) or promotes reverse trafficking of AQP2 (Aim 1C). In Aim 2, I will determine the physiologic function of GPR39 in wild-type (WT) and knockout (KO) animals under conditions of water restriction and rehydration after water restriction. To do this, I will quantify changes in parameters including drinking volume, plasma sodium, urinary osmolality, and urinary output in WT and KO animals at baseline and after intervention. In addition, I will perform molecular analyses on renal tissues to monitor changes in AQP2 expression, phosphorylation status, and localization. Together, the experiments in this proposal will provide key insight into both the mechanism (Aim 1) and the physiological role (Aim 2) that GPR39 plays in kidney physiology.

NIH Research Projects · FY 2026 · 2024-05

ABSTRACT This application aims to broaden the research expertise of Dr. Xu, who has a background in bioengineering, by delving into clinical research of neurodegenerative diseases. The goal is to support her pursuit of an independent research career focused on using advanced neuroimaging techniques to identify cognitive decline caused by vascular insults. It is increasingly recognized that cognitive decline in Alzheimer’s disease (AD) is influenced by factors beyond the plaques and tangles, including small vessel diseases. Vascular dysfunction seems to precede tissue atrophy resulting from neuronal degeneration, suggesting that measuring vascular function could insights into alternative pathologies contributing to early-stage cognitive dysfunction. Dr. Xu recently developed a non-invasive method of measuring arterial cerebral blood volume (CBVa) using the novel magnetic resonance imaging (MRI) technique called the Fourier transform-based (FT-) velocity-selective (VS) arterial spin labeling (ASL). In this proposed research, the FT-VS ASL will be applied to investigate the relationship between CBVa and cognitive function. To pursue this line of research, Dr. Xu will aim to bridge the gap between her engineering background and clinical dementia research through structured mentorship, acquiring clinical training from conferences and seminars, and conducting mentored research on the association between CBVa and cognitive function in individuals with mild cognitive impairment and mild dementia. The central hypothesis is that CBVa will be higher among those with MCI and mild dementia and higher CBVa will be associated with poorer cognitive performance. The hypothesis will be tested by pursuing three specific aims: (1) To refine the FT-VS ASL method for measuring CBVa. (2) To compare group differences in multi-compartment CBV (arterial vs total) among cognitively normal young and older (controls), individuals with MCI, and those with mild AD dementia. Additionally, to determine the cross-sectional association between CBVa and cognitive function in participants with normal cognition, MCI, and mild AD dementia. (3) To assess the association between longitudinal changes in cognitive function and CBVa. Upon completion of this research, the expected outcomes include the development of a robust non-invasive tool for quantifying regional CBVa. Furthermore, understanding the association between CBVa and cognitive function will shed light on the vascular contribution to dementia. These outcomes will form the foundation for a competitive R01 grant application, which will prepare Dr. Xu to become an independent investigator examining the merit of CBVa as a biomarker for dementia in a large cohort and comparing its efficacy with other biomarkers related to AD and related dementias (ADRD).

NIH Research Projects · FY 2026 · 2024-05

The Institute for Clinical and Translational Research (ICTR) Hub is a collaboration between universities in the Baltimore, MD area, including Johns Hopkins University (Hub lead), University of Maryland Baltimore (UMB), and Morgan State University (MSU). The ICTR supports research collaborations between universities and community-based health systems to address health problems important to the community. The overall vision of the ICTR Hub is to improve the health of the State of Maryland, with an emphasis on rural and urban areas where access to medical care and clinical research is low. The ICTR Hub will coordinate state-of-the-art precision medicine, population health, omics, imaging, and informatics to expand and harmonize translational research from our partner institutions in Maryland, reducing the health burden of acute and commonly co-occurring chronic conditions. The ICTR Hub will also elevate team science by integrating opportunities, resources, and infrastructure for cross-system and cross-university research; create trust and sustained partnerships within the community, including a strong patient-centered research focus; build new capacity for clinical research informatics, including new electronic medical record capabilities that support remote clinical trial work; provide integrated, comprehensive services; and develop new knowledge that benefits Maryland and the National CTSA consortium. In the next grant cycle, we will build on this successful foundation with the following Specific Aims.

NIH Research Projects · FY 2025 · 2024-05

Proposal Summary Globally, pregnant people from sub-Saharan Africa, including Malawi experience some of the highest rates of maternal and infant mortality (439 maternal deaths per 100,000 live births and 46 infant deaths per 1,000 live births) as well as high rates of psychological distress. For the health system to effectively reduce these poor outcomes, it is imperative that quality of care improves during the perinatal period. CenteringPregnancy, an innovative group antenatal care model recommended by the World Health Organization, addresses gaps in prenatal care and there is a growing evidence base of positive results. Community building is a core component of CenteringPregnancy, where women experience a dynamic process of connecting to their peers and their providers, through consistent group meetings throughout their pregnancy. However, this core component of the model is not well-defined. Therefore, the purpose of this mixed methods study is to understand community building in group antenatal care in Malawi. This study will use the research infrastructure and momentum of the ongoing NINR-funded (R01 NR018115) effectiveness trial for group based antenatal care in Blantyre district, Malawi, to complete a secondary data analysis of the parent study data as well as primary qualitative data collection. The specific aims are: Aim 1: Examine the differences in community building as measured by peer connectedness, provider connectedness, and partner communication, between the intervention and control group. Aim 2: Determine the difference in outcomes including psychological distress and birth outcomes, by community building between intervention and control groups. Aim 3: Explore how women perceive community building within group antenatal care and what changes, if any, they have experienced in related to community building, specifically in connectedness, communication and decision making within their relationship with providers, partner, family, and larger community. This study aligns with the National Institute of Nursing Research’s strategic goal of improving systems and models of care to advance women’s physical and mental health during pregnancy and postpartum. This training plan will begin a program of research focused on the promotion of the health and well-being of pregnant and postpartum women living in low-income settings. This study will inform the expansion of the effective intervention of group antenatal care both in the US and globally.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Human lung function is determined by a complex combination of both genetic and environmental factors. Temperature variation is an environmental factor with the potential to affect lung health on a large scale. While transient changes in local weather have been associated with increased rates of asthma and COPD exacerbations, less is known about the effects of temperature variation on long-term respiratory outcomes. A prior retrospective cross-sectional study has shown that warmer ambient air temperatures are associated with lower lung function in a general healthy U.S. population (NHANES). The primary goal of our proposal is to identify associations between changes in lung function and temperature variation over time by analyzing data from the U.S. Cystic Fibrosis (CF) Foundation Patient Registry, which includes longitudinal data from over 30,000 individuals with CF receiving care at accredited CF centers in the U.S. We are utilizing CF as a model as warmer ambient temperatures have been associated with lower lung function in 3 separate populations of individuals with CF in the U.S. and Australia, again through retrospective cross-sectional studies. Additionally, dense demographic and clinical information is collected routinely every three months for the entire lifetime of people with CF, which will facilitate this unique longitudinal study. In addition to testing whether temperature changes are associated with changes in lung function, we also plan to assess the roles of respiratory pathogens and socioeconomic factors in this relationship as well. Our methods include several different modeling approaches to account for subject mobility over time, non-linear temperature changes, CFTR modulator therapies, and time-varying confounders. We will also test approaches for interaction models (socioeconomic factors) and mediation models (respiratory pathogens). Completion of this research will provide information on the potential effects of temperature variation on long-term respiratory outcomes with relevance to respiratory morbidities and mortality as well as inform analytic techniques for future temperature studies of longitudinal outcomes. Understanding the effect of temperature variation on longitudinal outcomes is essential in quantifying the burden of disease that may be imposed by variations in ambient temperature.

NIH Research Projects · FY 2026 · 2024-05

Opioid use disorder (OUD) is a rapidly escalating public health crisis with recent evidence suggesting that close to 70% of drug overdose deaths involved opioids in the last year. Medications for OUD (MOUDs) such as buprenorphine and methadone are the frontline treatment for OUD, yet over half of individuals who initiate MOUD relapse or leave treatment in the first year, highlighting the importance of adjunctive therapies that might improve OUD treatment outcomes. Insomnia is a common and often recalcitrant issue among persons on MOUDs but there is little guidance on how to ameliorate symptoms of insomnia during OUD treatment. The orexin (or hypocretin) neurotransmitter system plays a role in insomnia and in the onset, progression, and maintenance of OUD. Suvorexant is a dual-orexin receptor antagonists that is FDA-approved for the treatment of insomnia, and data from our group suggests that suvorexant might be especially efficacious in treating insomnia in persons with OUD and may also confer collateral benefits including decreased opioid craving and symptoms of withdrawal. Moreover, suvorexant has an excellent safety profile and did not result in increased adverse events or measures of abuse potential when compared to placebo in our pilot study. The proposed study is an FDA-regulatory-grade Phase III multisite randomized-controlled trial of suvorexant versus placebo in persons with insomnia who are utilizing long-term MOUD treatment. Participants who are prescribed buprenorphine or methadone for OUD will be screened to determine study eligibility. Eligible individuals will be enrolled for an 8-week study that includes the following conditions: one night double-dummy placebo lead-in prior to randomization; ~8 weeks of suvorexant or placebo where the dose may be escalated from 10 mg to 20 mg after 3 nights (consistent with current suvorexant label instructions); and two-nights double-dummy placebo lead-out to examine discontinuation effects. In lab polysomnography (PSG) will be used to at the beginning and end of the trial to determine the primary endpoint of change from baseline total sleep time. Adverse events and other indicators of patient safety will be monitored throughout the study. Participants will also be assessed for OUD treatment outcomes including regular urine toxicology and trajectories of mental health during the study. Specific Aims of the study are to (Aim 1) evaluate the efficacy of suvorexant versus placebo in treat insomnia in persons taking buprenorphine or methadone for OUD treatment, (Aim1) Evaluate the safety of suvorexant versus placebo in persons taking buprenorphine or methadone for OUD treatment, (Aim 3) submit a Supplement Application of Efficacy to the FDA to support an update to the label of suvorexant, and (Exploratory Aim 4) determine whether suvorexant versus placebo improves OUD treatment outcomes. The results of this important study will inform treatment providers on whether suvorexant is safe and effective for insomnia in persons with OUD, and exploratory results will further our scientific understanding of the role of the orexin system in OUD treatment and recovery.

NIH Research Projects · FY 2026 · 2024-05

This longitudinal, mixed methods study investigates the relationship between disaster-related stressors, social determinants of health, and health outcomes among HIV-positive people who use drugs (PWUD) in Ukraine and the strategies that health and social service providers have adopted to maintain access to care. In Ukraine, people who use drugs (PWUD) and live with HIV are a vulnerable population and at least 38% of all people with a new HIV diagnosis and at least 50% of all people living with HIV (PLWH) indicate injection drug use as the route of transmission. The war in Ukraine that began in February 2022 precipitated massive immediate and potentially long-term disruptions to all aspects of daily life in Ukraine, with unknown consequences for HIV-positive PWUD. War is both a disaster and a form of mass trauma that involves widespread destruction, loss of life, and psychological distress for those directly and indirectly affected by it. The impact of mass traumas may have disproportionately negative consequences for already vulnerable populations, including those who are economically precarious and socially marginalized. Social determinants of health—the social conditions and economic circumstances that influence health—are key contributors to HIV care and treatment outcomes. The specific aims of this study are: (1) To measure the effects of disaster-related stressors (personal, interpersonal, and environmental) and mediating effects of SDOH and adaptation on primary clinical outcomes of HIV care engagement, ART adherence, and viral suppression and secondary outcomes of drug treatment engagement and risky substance use in a longitudinal cohort followed up to 3 years; (2) To qualitatively characterize at baseline and longitudinally the effects of conflict on social determinants of health and adaptation trajectories of HIV-positive PWUD; and (3) To explore how service providers who work with PWUD and PLWH modify policies and practices in the context of supply chain disruptions, workforce depletion, and population displacement to promote continued care engagement. This project will use an innovative instrumental variables approach to assess how mass trauma and resulting changes to SDOH causally affect substance use and HIV outcomes and link these findings to structural and resources changes that resulted from the war. This approach will leverage a natural experiment in which residence in areas of Ukraine most affected by the war (proximal to the frontlines) approximates a random assignment to mass trauma exposure. Identifying how people remain connected to HIV and substance use care in contexts of disruption and the strategies that health care and social service providers use to keep people engaged have potential broad transferability. The immediate and longer-term consequences of mass trauma for HIV outcomes are unknown. Identifying how people remain connected to HIV care in contexts of disruption and the strategies that health care and social service providers use to keep people engaged have potential broad transferability.

NIH Research Projects · FY 2026 · 2024-05

The overall goal of this two-phase (R61/R33) study is to build capacity in the behavioral health workforce (BHW) by training them to deliver an evidence-based police education program to reduce HIV risk among people who use drugs (PWUD). A robust evidence-base indicates certain policing practices, such as arrest, can elevate overdose and infectious disease risk by preventing access to life-saving medications. Despite police officers having wide discretion when responding to drug-related offenses, arrest and incarceration rates of PWUD remain high, which in turn increase rates of HIV, HCV, and overdose. This study will help fill a critical gap in the science to examine the impact and scalability of a policy-level HIV prevention intervention that shifts policing away from arrest and toward referral to evidence-based medications for opioid use disorder (MOUD). The Safety and Health Integration in the Enforcement of Laws on Drugs (SHIELD) is a police education program that has been implemented in numerous U.S. jurisdictions that focuses on reducing occupational risks and burnout among police, and task-shifting to increase referrals to essential services for PWUD, such as MOUD. Thus far, delivery of SHIELD has relied on a specialized academic team limiting its scalability. In this study, we will move SHIELD into the hands of the BHW to implement “SHIELD 2.0” in a region of Appalachia that has been hard hit by overlapping epidemics of overdose and blood-borne virus transmission. Evaluating the implementation and effectiveness of this approach will be a critical step towards SHIELD 2.0 scalability and population impact. We will leverage the infrastructure of an ongoing cohort of approximately 500 PWUD (R01DA033862) in Kentucky to externally validate SHIELD 2.0. In the first year of this study (R61 phase), we will rapidly assess BHW acceptability and readiness to deliver a SHIELD 2.0 to police (Aim 1) and adapt and pilot the SHIELD 2.0 implementation strategy to assess its feasibility and acceptability (Aim 2). In the R33 phase, we will then conduct a Type 2 hybrid implementation-effectiveness study to evaluate the SHIELD 2.0 implementation model (n=150) (Aim 3), and determine the effectiveness and cost-effectiveness of SHIELD 2.0 (Aim 4). We will evaluate this by leveraging county-level administrative substance use data and laboratory-measured hepatitis C incidence from large ongoing NIH-funded cohorts. Outcomes will include fatal and non-fatal overdose rates, emergency department visits, and MOUD utilization and retention. Surrogate endpoints include police referral to behavioral health services. We expect findings from this study to be high-impact and would visibly transform policing to reduce health outcomes that disproportionately affect PWUD. Further, enhancing the role of law enforcement agencies to reduce HIV/HCV risk through enhancing access to HIV/HCV prevention services, such as MOUD, is a major interagency priority of the Department of Health and Human Services, DOJ, and the Office of National AIDS Policy.

NIH Research Projects · FY 2025 · 2024-05

Summary The selective absence of IgM in humans, a rare genetic disorder, is linked to enhanced autoimmunity, as well as increased risk of infections, consistent with studies in mice. In mice, most spontaneously generated “natural” IgM is produced by broadly autoreactive B-1 cells, cells that develop in multiple waves during the fetal and early neonatal period, through a developmental path that is controlled in part by epigenetically regulators of fetal hematopoiesis (Lin28/Let7). Their distinct developmental processes select for a unique and self-reactive Ig- repertoire that characterizes these B-1 cells, which in turn defines their transcriptional profile. Our recent studies have identified two distinct subsets of nIgM-secreting B-1 cells in bone marrow and spleen: B-1 plasma cells (B- 1PC) and non-terminally differentiated B-1 cells (B-1sec). The distinct pathways these cells take to becoming nIgM-producing cells, and thus the mechanisms controlling these autoreactive, yet functionally critical nIgM- secreting B cell subsets, is largely unknown. Filling this gap in knowledge is important as it may identify novel control mechanisms of B cell-mediated autoimmunity, guide the identification of human B-1 orthologues, and eventually their manipulation for therapeutic or prophylactic uses. We have been involved in a large-scale phenotypic reverse genetics screening effort of 14 weeks-old C57BL/6 mice with single, known gene deficiencies (“knockouts”), generated by an NIH-supported consortium. We used two multicolor flow cytometric panels to screen the spleens of 4,390 mice (3F/3M mice per genotype) and 617 distinct genotypes for changes in leukocyte populations. Using an unbiased data analysis approach, we recently identified 18 knockout mice with significant and selective changes in splenic B-1 cells. 17 of those have not previously been shown to affect B cell development or differentiation. One, Rac-2 was previously shown to affect B-1 and marginal zone B cells demonstrated the validity of our approach. Aim 1 of this application is to explore the functional impact of 7 of these novel genes on the development of B cell subsets, especially the nIgM-secreting B-1PC and B-1sec in spleen and bone marrow and their B cell extrinsic and intrinsic expression. In Aim 2 we propose to study the functional impact of the genes, by measuring antibody production from birth – 14 weeks of age by ELISA and ELISpot and assessing the repertoire via auto-antigen array. Neonatal allotype-chimera approaches will determine to which extent validated genes regulates B-1 cells and their differentiated nIgM secreters in a B cell- intrinsic versus extrinsic manner. Expected results would identify novel genes and/or regulatory pathways selectively responsible for the regulation of natural Ig production. This would enable future follow-up studies to define the molecular mechanisms by which each of the identified genes regulate these cells and might help to develop gene-signatures that could aid the identification of B-1 orthologues in humans or other model species. It may also reveal pathways that more broadly control antibody production by autoreactive B cells.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Vertebral compression fractures (VCFs) are effectively treated with vertebral augmentation (VA), which rapidly reduces pain and restores function. The most significant opportunities to advance VA as an efficacious treatment option for (cancer) patients in acute pain are to 1) considerably reduce radiation dose to patient and staff; 2) improve the safety of VA; and 3) increase its efficacy by establishing superior but more complex techniques using curved instruments. Introducing robotic systems for VA will address these three significant challenges. However, existing robotic solutions are bulky, expensive to acquire and maintain, and disrupt workflows. These drawbacks make current systems inadequate for VA, a quick procedure that is often performed in outpatient settings. To capitalize on the benefits of robotics for VA – reduced radiation dose and complication rates, and increased efficacy – novel, alternative robotic platforms and corresponding algorithms are needed that seamlessly integrate with the VA workflow, enable robot planning from interventional X-ray images, and are more affordable. Our long-term goal is to advance surgical robotics technology for X-ray-guided VA by developing 1) a novel class of tool-mounted robots, 2) a suite of powerful image-based algorithms for automated intra-operative surgical planning, verification, and closed loop control, and 3) mixed reality interfaces for remote actuation and assurance. Because our robotic solution augments the conventional VA workflow and its tools, and is of considerably lower cost than existing robotic solutions, our developments will contribute to unlocking the known benefits of surgical robotics for the surgical treatment of the tens of thousands of VAs that are performed across a wide variety of providers every year in the US. Our specific aims are: 1) Develop and test a cannula- mounted piezo robot for image-guided VA: We will create a cannula-mounted piezo robot, supported by a passive positioning arm, that meets the clinical requirements of VA. The robot will combine high accuracy and force with a low-profile design to not interfere with X-ray image-guidance. 2) Develop imaging and planning algorithms, and user feedback to guide delivery: We will develop algorithms for a camera-augmented C-arm X-ray system to acquire and interpret X-ray and RGB-D images to achieve automated planning and guidance. Via mixed reality, they will guide providers through the semi-automated workflow to ensure safe and accurate execution. 3) Demonstrate integrated system performance ex vivo: We will confirm the functional performance, reliability, and overall system accuracy of our robotic approach through a series of cadaver studies. Our multi-disciplinary team will be the first to investigate tool-mounted robots for hard-tissue surgery, paving the way for a new family of robots that are compact and exert sufficient force for bone surgery. Combin- ing innovative robotic actuators with powerful algorithms for automated planning and remote-actuation will provide alternative robotic solutions that will contribute to a more widespread adoption of robotic surgery.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Premenopausal females have blood pressure that is ~10mmHg lower than that of males. We previously reported that an evolutionarily conserved olfactory receptor, OLFR558, is expressed in the kidney. We have now found that sex differences in blood pressure are absent in Olfr558 knockout (KO) mice, primarily due to increased blood pressure in females, along with a decreased diastolic pressure in males. In Aim 1, we will determine which OLFR558-expressing cell types are primarily responsible for the blood pressure phenotype in males and females. OLFR558 is expressed both in the vasculature and in the renal afferent arteriole (where renin is stored and secreted from); thus, we will examine both renin levels and vascular responses in male and female whole-animal KO mice. In addition, we will examine these same parameters, along with blood pressure by telemetry, in mice with tissue-specific Olfr558 rescue only in the vasculature, or, only in renin-expressing cells. In Aim 2, we will use gonadectomy in wild-type and KO mice to test the hypothesis that OLFR558 relies on gonadal signals to mediate sex differences. In parallel experiments we will use the four core genotype model, in which gonadal and chromosomal sex are separately inherited, to further interrogate this hypothesis. Finally, it is well-established that males have a higher incidence of hypertension than premenopausal females; this is true both in humans, and, in animal models of hypertension. In Aim 3, we will examine how OLFR558 influences sex differences in hypertension using two different hypertension models (Angiotensin II infusion, and, DOCA/Salt). In sum, these studies will reveal key insights into the function of an evolutionarily conserved OR which is required for sex differences in blood pressure.

NIH Research Projects · FY 2024 · 2024-05

Overall Abstract Prostate, breast and pancreatic cancers all have a disproportionately higher rate of aggressive tumor grade and early onset in Black patients, with recent spikes of high incidence in west African nations compared to other African regions. The genetic background correlations implicate predispositions. Members of our SAMBAI team of investigators have pioneered genomics in cancer disparities research and over the past two decades we have uncovered compelling evidence of distinct immunological mechanisms associated with genetic ancestry. Our SAMBAI team members have developed methods to quantify environmental exposures and interrogate lived experiences of marginalized populations including epigenetic responses racism. Aims We will partner with scientists across the US, Africa and the UK to build an unprecedented resource, the SAMBAI Biobank and Data Repository for Cancer Equity Research. We will generate a comprehensive, accurate and relevant measurement of social, environmental, genetic and immunological factors to complete an integrated set of analyses to define the causal vs. modifier relationships of disparate outcomes in diverse underserved populations. We will establish a sustainable framework for team science approaches with under- represented partners and establish best practices for coordinating cancer equity research on a global scale. Methods We propose to utilize multiple methods across our different work packages. Social Determinants includes self- reporting surveys and database abstractions. Exposomes utilize mass spectrometry of plasma. Genomics will utilize three sequencing methods on germline and tumor tissue, including long-read, short/deep and ultra-low pass whole genome sequencing. Lastly, immunological profiles will be measured with spatial transcriptomics and circulating multiplex immunoassays. These data require novel computational frameworks, including cloud- based virtualization and use of machine learning technologies to identify novel associations across the strata of social to spatial data elements and across our diverse geographic and ancestral SAMBAI cohorts. Utility and Impact We will improve research capacity in under-resourced environments for large scale cancer research and equitable access to data with equitable feasibility to improve treatment and outcomes. We will define interactions of environmental exposures, social determinants, and genetic ancestry that determine immunological landscapes of primary tumors and/or circulating immunological profiles in patients of African descent. Our project will contribute a data repository with 100K features/patient, for 40,000 patients. The impact to this population includes a novel trial design, in collaboration with our patient advocacy partners, to ensure that the specific genomic and immunological features we uncover become part of targeted precision oncology theragnostic options