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Patch for hemodynamic and hemorrhage monitoring

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NIA - National Institute on Aging

PROJECT SUMMARY/ABSTRACT Trauma remains a leading cause of death globally, with hemorrhage being a significant contributor. The need for improved trauma care and management is evident, especially in reducing mortality related to hemorrhagic shock and addressing racial disparities in trauma outcomes. This project aims to develop a novel, integrated, wearable hemodynamic platform (iMOMS) designed for the early detection and management of hemorrhage, leveraging advancements in Micro-Electro-Mechanical Systems (MEMS), laser speckle imaging (LSI), and diffuse optical spectroscopy (DOS). By integrating these technologies with machine learning algorithms, iMOMS promises to enhance trauma care through improved monitoring of vital signs and hemodynamic parameters, thus facilitating timely interventions. We will pursue the following Aims: 1) Validate the iMOMS platform in a rabbit model of hemorrhage, focusing on the accurate, continuous measurement of vital signs and hemodynamic parameters. This aim tests iMOMS' ability to monitor and record heart rate, blood pressure, cardiac output, blood flow, hemoglobin oxygen saturation, and oxygen consumption during controlled hemorrhage, leveraging the rabbit model's physiological similarities to humans. 2) Develop and refine a machine learning model to predict hemorrhage by integrating multimodal data streams from humans and rabbits. This includes building an MMML model to identify early indicators of hypovolemia and creating a model for more accurate hemorrhage prediction in humans through transfer learning and domain adaptation from the animal model. 3) Test the iMOMS prototype and ML model in the operating room on patients at high risk for hemorrhage. This includes determining the accuracy of monitored vital signs and testing and refining the ML model developed in Aim 2 for predicting hemorrhage in various surgical patients. The successful completion of this project is expected to have a significant impact on trauma care by providing a reliable, non-invasive, and comprehensive monitoring system capable of early hemorrhage detection. By improving the accuracy and timeliness of interventions, iMOMS has the potential to save lives and advance the field of trauma management significantly.

Up to $409K

Deadline: 2028-01-31

Health

Pathogenesis of Permanent Neurological Disability in Multiple Sclerosis

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NINDS - National Institute of Neurological Disorders and Stroke

Project Summary Multiple sclerosis (MS), an immune-mediated demyelinating disease of the human central nervous system, afflicts over 2.5 million people worldwide and is the leading cause of non-traumatic neurological disability in young adults. Most people with MS (PwMS) have a clinical course initially characterized by relapses and remissions (RRMS) that eventually evolves into a progressive course (PMS) where relapses are rare, and disability progression is continuous and irreversible. While it is usually assumed that neurodegeneration results from demyelination, accumulating evidence supports the concept that disability worsening in MS is caused by an insidious neurodegenerative process that can occur independent of relapses and cerebral white matter (WM) demyelination. One intriguing mechanism for neurodegeneration independent of demyelination is surface-in gradients of brain pathology identified by brain imaging studies of PwMS and pathological studies of postmortem MS brains. The main objective of this proposal is to identify cellular and molecular alterations in postmortem MS brains that are responsible for surface-in gradients of myelinated fiber degeneration at the posterior horn of the lateral ventricle, and neuronal and synaptic loss at the pial surface of the cerebral cortex. We recently described a surface-in gradient of myelinated axonal degeneration at the occipital horn of the lateral ventricle. Preliminary studies identified transcript alterations in ependymal cells from postmortem MS brains that correlate with pathological changes that compromise this ependymal cell barrier, identified increased cerebrospinal fluid (CSF) proteins from progressive MS patients that bind to the upregulated ependymal cell surface receptors, and identified a surface-in gradient of oligodendrocyte pathology. Specific Aim 1 will extend these observations by investigating whether a surface-in gradient of oligodendrocyte transcript changes occurs, whether oligodendrocytes express receptors for increased CSF components, and if increased CSF components with ependymal and oligodendrocyte receptors compromise ependymal cells and/or oligodendrocytes in vitro. A surface-in gradient is a likely explanation for the global nature of cortical atrophy found in most PwMS. While pathological and brain imaging studies have identified cortical surface-in gradients, molecular characterization of the mechanism causing this gradient has not been reported. Specific Aim 2 will investigate if pial matter transcripts are altered in MS brain, and whether CSF from PwMS contain upregulated proteins that bind to pial surface proteins. The human cerebral cortex contains a unique population of subpial interlaminar astrocytes that reside in cortical layer I and send multiple apical processes to the pial surface and multiple basal processes that descend into cortical layers II-IV and often associate with activated astrocytes that are associated with cortical vessels. Since these cells are positioned for long-distance communication between CSF and intracortical cells, we will investigate pathological and transcriptional changes in interlaminar astrocytes in MS cortex.

Up to $545K

Deadline: 2030-12-31

Health

Pathogenesis of the concentric hypertrophy of the kidney arterioles

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NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT More than 30% of the US population suffers from hypertension, a leading cause of morbidity and mortality due to cardiovascular and kidney disease. Inhibitors of the renin-angiotensin system (iRAS) are used widely and effectively to treat hypertension. However, chronic stimulation of the renin cells, with iRAS or mutations of any of the renin angiotensin genes leads to concentric arterial and arteriolar hypertrophy (CAAH) a silent, progressive, generalized, and severe thickening of the intrarenal arterial tree. Numerous hypertrophic renin cells surround the arteriolar walls, smooth muscle cells (SMCs) accumulate inwardly, narrowing the vessel lumens and restricting blood flow, resulting in ischemia, fibrosis, and renal failure. Despite its medical importance and the prevalent use of iRAS to treat hypertension, our knowledge of this disease is limited. The condition is intimately linked to the development of renin cells: they are progenitors of SMCs, mesangial cells and pericytes which retain the memory of -and transform to- the renin phenotype in response to homeostatic challenges. Genetic ablation of renin cells prevents the arterial disease indicating that renin cells are responsible by the production of factors that induce the vascular hypertrophy. We found that renin cells produce nerve growth factor (NGF), a powerful guiding molecule that attracts axons to target cells, including renin cells which are exquisitely innervated by thin axons that follow closely the developing arterioles and emit varicosities at the point of contact with the cells. It is likely that innervation regulates the differentiation and fate of renin cells both during arteriolar development and disease. In fact, the diseased vessels are hyper-innervated: numerous and thickened axons wrap around the entire kidney vasculature. As the disease progresses, the arteriolar cells change fate, filtration declines, and new axons arise, transforming the kidney into a pathological neuro-endocrine organ. Our overall hypothesis is that morphogenesis and fate of the renal arterial tree during development and disease are intimately linked and dependent on the co-inductive interactions between nerve fibers and renin cells and their descendants. Using proven tools already developed in our laboratories (novel cell-specific fluorescent reporter mice, 3D imaging, 2-photon microscopy, immuno-EM, innovative surgical techniques, spatial transcriptomics, and time- and cell specific gene deletion studies) we propose to test the following hypotheses: 1. development of the renal arterial tree is coupled with the timely establishment of unique nerve fibers and cell type-specific synapses, 2. innervation and blood flow are necessary for the development of the kidney vasculature and 3. hyperinnervation of the kidney vasculature and NGF are responsible for the CAAH and the transformation of the kidney into a pathological neuro-endocrine organ. This dual PI application composed of a team of experts, based on compelling preliminary data and novel conceptual and technical approaches, will uncover fundamental mechanisms, and solve major gaps in our knowledge that will open new avenues for the development of novel compounds and strategies to protect the kidney while preventing cardiovascular disease.

Up to $798K

Deadline: 2030-01-31

health research

Pathophysiology of Severe Yellow Fever

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NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Yellow fever (YF) is a serious mosquito-borne disease (~80,000 deaths annually) endemic to Africa and South America that is poised for emergence/re-emergence on a global scale. YF is caused by the yellow fever virus (YFV), which replicates primarily in the liver where it causes significant damage and organ dysfunction. Although treatment of YF is limited to supportive care, a highly effective live-attenuated YF vaccine (known as “17D”) was created in the 1930s. 17D differs from its parental strain, “Asibi,” by only 22 amino acids; however, the mutations responsible for the attenuation of 17D remain unknown. A major barrier to understanding 17D attenuation and YF pathogenesis is the lack of an immunocompetent small animal model that faithfully recapitulates important aspects of human YF disease. In collaboration with physicians and pathologists in Brazil, we have shown that infection of hamsters with hamster-adapted YFV-Asibi recapitulates human YF extremely accurately. Using this model, we have begun to tackle the most pressing questions in the YFV field. We developed a highly flexible reverse genetics system for YFV that enabled us to create large panels of hamster-adapted (HA)-17D/Asibi chimeric viruses. Using disease in the hamster as our primary readout, we identified two mutations in17D’s NS2B gene that, when introduced into HA-Asibi, completely abolish YF disease but have a relatively small impact on viral replication. It is well established that YFV-Asibi and YFV-17D evoke significantly different antiviral type I interferon (IFN) response, with YFV-17D inducing significantly more IFN than YFV-Asibi. Therefore, in Aim 1, we will first study the relationship between these two NS2B mutations, IFN induction, viral replication, and attenuation. We will determine the molecular basis for differential IFN responses between YFV-Asibi and YFV-17D. And finally, we will identify and characterize the innate immune factors that are antagonized by virulent, but not attenuated, YFV. Using the hamster model and specimens collected from YF patients in Brazil, we recently discovered that gastrointestinal (GI) damage plays a central role in the development of YF intoxication by allowing gut bacteria to opportunistically spread within the virus-ravaged host. Thus, intoxication is a septic-shock-like syndrome. There is now an urgent need to understand the drivers of GI damage in YF. Our preliminary studies have shown that YFV does not infect cells in the GI tract. Therefore, in Aim 2, we will seek to understand how YFV infection causes severe GI damage. First, we will determine the anatomical distribution of GI damage in the hamster model. Next, we will determine the anatomic distribution of vascular damage in YF. And finally, we will determine if the viral toxin NS1 is responsible for causing YFV-mediated GI damage. This project integrates viral genetics, antiviral immunity, and recent insights into YF intoxication into a new unified mechanism of YFV pathogenesis. This research has real-world implications for improving vaccine safety/efficacy and developing interventions aimed at reducing the morbidity and mortality of YF.

Up to $729K

Deadline: 2031-01-31

Health

Patient Outcomes and Health Care Use in U.S. Hospices After Private Equity Acquisition

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NIA - National Institute on Aging

Hospice care is increasingly important for 67 million Medicare beneficiaries in the U.S.—accounting for a quarter of Medicare spending. At the same time, hospices across the U.S. are increasingly acquired by private equity (PE) firms. Over the last 20 years, half of U.S. hospices have turned from non-profit to for-profit status, with PE driving the recent increase. To date, the clinical and economic effects of PE acquisitions remain poorly understood—both on average and across subgroups. Recent evidence on PE from other parts of the delivery system including hospitals, nursing homes, and physician practices show that PE acquisition is associated with changes in patient selection, increased adverse events (hospitals) and mortality (nursing homes), along with increased charges, prices, and spending. To date, evidence of its impact in hospice remains sparse. Rigorous evidence on PE's effects on hospice patient selection, utilization, and outcomes is urgently needed. PE firms have several strategies to maximize revenues from hospice facilities, given that hospice payment by Medicare (the main payer for hospice) is a per diem (day), non-risk-adjusted fee. We hypothesize that PE acquisition leads to selection of lower-risk or healthier Medicare patients, who are more likely to exhibit longer lengths of stay on hospice while using less care (fewer visits and services) on average. We hypothesize that, on average, PE acquisition leads to an increase in the live discharge rate, shifts toward lower-cost modalities of hospice (e.g. home hospice rather than facility-based), and increased Medicare spending. Via a hypothesis- driven approach, this project focuses on these key mechanisms by which PE firms may alter hospice behavior, using a novel dataset of hospice PE acquisitions linked to 100% CMS Medicare data spanning 2016-2018. To better approach causal inference, we use a quasi-experimental design that incorporates more novel statistical innovations in matching and weighting to derive two distinct, but related, counterfactuals of non-PE hospices: hospices that are non-profit and hospices that are for-profit but not PE-owned. Using rigorous methods, we will also examine treatment effect heterogeneity by patient and hospice characteristics. Understanding the mechanisms by which PE affects U.S. hospice care could inform policies that mitigate undesirable consequences for patients, including access to hospice, and help protect the solvency of Medicare going forward. Findings will contribute to a nascent scientific literature on PE's effects on hospice, which is key for the aging U.S. population, and will continue to be policy relevant as federal and state governments consider ways to protect patients and clinicians from the undesirable implications of PE. Given the labor-intensive effort required to collect and verify data on PE acquisitions, we will also make publicly available a novel database of PE-acquired hospices in the U.S. Our research aims support the NIA strategic objectives for research and the aging population, including improving the health and wellbeing of older adults (Goals C, E, F) and using evidence to inform stewardship of public resources (Goals H, I).

Up to $684K

Deadline: 2031-01-31

Health

Patient-specific, combinatorial NAMs for gastrointestinal diseases and drug response prediction

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OD - NIH Office of the Director

ABSTRACT Millions of people in the US are impacted by gastrointestinal diseases including Inflammatory Bowel Disease (IBD), Metabolic Disfunction Associated Steatotic Liver Disease (MASLD) and Pancreatitis. There are only a small number of drugs for IBD and MASLD, and none for Pancreatitis, making this a critically significant clinical question. Animal models have proven inadequate surrogates for these diseases and reliance on current preclinical evaluations are considered to be among the most problematic steps in drug discovery. The goal of Cincinnati Advanced NAM Development and Operational Research center (CANDOR) is to develop combinatorial New Approach Methodologies (NAMs) that more accurately model the pathophysiologic complexity and drug responses in patients with these gastrointestinal (GI) diseases. We have established an interdisciplinary team of collaborators of clinicians, scientists, experimental and computational biologists with a history of developing in vitro organoid and in silico NAMs with a focus on inflammatory diseases of the GI tract. CANDOR will provide a collaborative pipeline starting with existing cohorts of deeply phenotyped patients with IBD, MASLD, and Pancreatitis. Clinical data and patient samples will be used to build in silico NAMs, based on molecular pathways and cell-cell interactions that corelate with patient outcome and drug response. Each disease will have a corresponding in vitro NAM comprising intestinal, liver, and pancreatic organoids each with immune cells. Pluripotent stem cell banks have been generated from patients with each of these diseases, and healthy controls, and all organoid platforms are established and benchmarked to human samples. The aims of CANDOR are to establish in vitro NAMs that accurately model clinical features of IBD, MASLD, and Pancreatitis; to build disease-focused in silico NAMs that are based on gene regulatory, cell-cell interactions, and pharmacometric models from patients and combine these with data from in vitro NAMs; and to validate and disseminate combinatorial NAM technologies through training, outreach, and distribution.

Up to $3.2M

Deadline: 2030-12-31

Health

PD-1H Signaling in the Regulation of the Tissue Immune Microenvironment of Lupus

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NIAID - National Institute of Allergy and Infectious Diseases

SUMMARY Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by systemic immune dysregulation, with lupus nephritis (LN) being one of its most severe manifestations. While systemic immune abnormalities in lupus are well recognized, the immune landscape within lupus-affected tissues remains poorly characterized, and the role of immune checkpoint-mediated regulation in autoimmune microenvironments is a critical yet largely unexamined frontier. PD-1H (Programmed Death-1 Homolog, also known as VISTA) is a unique immune checkpoint expressed on both T cells and myeloid cells, functioning as a key regulator of immune suppression. Our preliminary studies reveal that PD-1H deficiency leads to spontaneous autoimmunity resembling lupus, and PD-1H is upregulated in lupus-affected tissues, suggesting its critical role in local immune regulation. These findings set the stage for investigating how PD-1H regulates immune pathogenesis in lupus and evaluating PD-1H-targeted immune checkpoint activators (ICAs) as a novel therapeutic approach. Aim 1 will determine the role and mechanisms of PD-1H signaling in the regulation of pathogenesis in the lupus affected tissue microenvironment. We hypothesize that PD-1H functions as a checkpoint receptor on pathogenic T cells and anti-inflammatory macrophages, mitigating inflammation and reducing tissue damage. To test this, we will (1) map the spatial distribution of PD-1H in kidney and skin biopsies from lupus patients using multiplex immunofluorescence and spatial transcriptomics and (2) determine how PD-1H regulates immune infiltration and modulates pathogenic immune activity using induced lupus models in tissue-specific PD-1H- deficient mice. Furthermore, our preliminary studies reveal that PD-1H interacts with key kinases in T cell receptor (TCR) signaling. We hypothesize that this interaction mediates PD-1H’s inhibitory effects on T cell activation, which we will test using structural mutants, co-immunoprecipitation assays, and phosphor-proteomics- based analyses to map PD-1H-regulated signaling networks in lupus pathogenesis. Aim 2 will Develop Novel Therapeutic Strategies for Lupus Using PD-1H Immune Checkpoint Activator (ICA). We will assess the efficacy of mouse PD-1H ICA in lupus and LN models, performing functional assays to determine its impact on T cell suppression and macrophage modulation. To advance these findings toward clinical translation, we will evaluate the effects of a newly developed human PD-1H ICA in a lupus patient-derived xenograft (PDX) model. These studies will establish PD-1H ICA as a novel strategy to modulate autoimmune pathogenesis while preserving immune homeostasis. This project integrates mechanistic studies with innovative therapeutic strategies to establish PD-1H as an essential regulator of lupus pathogenesis. These findings will not only reshape our understanding of immune regulation in lupus but also provide a foundation for developing next-generation immune checkpoint-targeted therapies for autoimmune diseases.

Up to $584K

Deadline: 2031-01-31

Health

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