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Immune Modulation in Hypertension

高血压的免疫调节

基本信息

批准号：
10521590
负责人：
Meenakshi Swaminathan Madhur
金额：
$ 63.45万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-10 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521590
关键词：
Acetates Address Adoptive Transfer Adult Affect Angiotensin II Anti-Inflammatory Agents Antigens Antihypertensive Agents Autoimmune Diseases Blood Pressure Blood Vessels Cardiometabolic Disease Cardiovascular system Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Chronic Kidney Failure DOCA Data Deoxycorticosterone Development Endothelial Cells Equilibrium Etiology Event Fibrosis Functional disorder Heart Heart failure Helper-Inducer T-Lymphocyte Human Hypertension IRF4 gene Immune Immune system Immunodeficient Mouse Immunology procedure Immunosuppression Individual Infection Inflammation Inflammatory Injury Interleukin-17 Interleukins Kidney Knockout Mice Lead Leukocytes Lipopolysaccharides Malignant Neoplasms Mediating Modeling Molecular Morbidity - disease rate Mus Myocardial Infarction Oral Organ Pathway interactions Patient Care Patients Persons Phase II/III Clinical Trial Phenotype Phosphorylation Prevention Protocols Production Protein Kinase Public Health Reagent Regulatory T-Lymphocyte Risk Factors Rodent Model Role STAT3 gene Safety Signal Transduction Sodium Stat5 protein Stimulus Stroke T cell differentiation T cell therapy T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Therapeutic Therapeutic immunosuppression Translating Treatment Protocols Work blood pressure reduction cardiovascular risk factor cell type cytokine endothelial dysfunction humanized mouse hypertension treatment hypertensive immune activation immune function immunomodulatory therapies immunoregulation in vivo infection risk inhibitor kidney vascular structure mortality new therapeutic target normotensive novel novel diagnostics novel marker peripheral blood potential biomarker prevent response rho salt sensitive hypertension systemic inflammatory response therapeutic target tissue injury translational study vascular inflammation

项目摘要

PROJECT SUMMARY Hypertensive stimuli activate innate and adaptive immune cells which then act on target organs such as the kidney and vasculature causing tissue injury/inflammation and hypertensive end-organ damage. We and others have shown that depleting subsets of immune cells or individual cytokines in rodent models is indeed protective against these deleterious effects of hypertension. Yet there are currently no immunomodulatory therapies for hypertension, which affects nearly 50% of adults worldwide. A major reason for this is that immunosuppressive therapies would render a large percentage of people susceptible to infection and malignancy. A final common pathway of immune activation in experimental and human hypertension is the skewing of T cell subsets towards pro-inflammatory T helper 17 (Th17) cells, which secrete interleukin 17A (IL-17A) and IL-21, and away from anti- inflammatory regulatory T cells (Treg). There is emerging evidence that Rho-associated protein kinase 2 (ROCK2) acts as a molecular switch in T helper cells by promoting Th17 differentiation, via phosphorylation of STAT3 and IRF4, and inhibiting Treg differentiation. In this proposal, we will test the novel hypothesis that hypertension is associated with activation of a ROCK2/STAT3/IRF4 pathway in T cells that leads to increased Th17/Treg ratios and exacerbated hypertension and inflammatory damage. Furthermore, we propose that selectively inhibiting ROCK2 will restore a homeostatic T cell balance without causing global immunosuppression. A novel orally bioavailable selective ROCK2 inhibitor, KD025, has completed phase 2/3 clinical trials for IL-17A/IL-21 mediated autoimmune diseases with a favorable safety profile and no apparent increased risk of infection. We have novel preliminary data that KD025 significantly reduces BP and increases Treg/Th17 cell ratios in the kidney in response to experimental hypertension. In Aim 1 of this proposal, we will use inducible conditional ROCK2 deficient mice to determine cell-specific roles of ROCK2 in hypertension. To determine whether T cell ROCK2 deletion restores the Th17/Treg balance in hypertension with minimal effects on other cell types, we will use a novel single cell technique, called CITE-Seq, to phenotype circulating leukocytes as well as perform functional assays of immune function using a lipopolysaccharide (LPS) model of systemic inflammation. In Aim 2, we will determine the effect of KD025 on BP, Th17/Treg balance, end-organ damage, and LPS-induced inflammation in response to hypertensive stimuli. In Aim 3, we will use peripheral blood T cells from normotensive and hypertensive humans to determine whether T cell ROCK2 activity is increased in hypertension. To determine causality, we will adoptively transfer T cells from humans into immunodeficient mice to determine whether human T cells promote hypertension and renal/vascular inflammation in a ROCK2 dependent manner in humanized mice. Our team is uniquely poised to conduct these translational studies that will potentially transform immunomodulatory therapies for hypertension and its associated complications.

项目总结