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.

项目摘要高血压刺激激活先天和适应性免疫细胞，然后作用于靶器官，例如肾脏和脉管系统导致组织损伤/炎症和高血压最终器官损伤。我们和其他人已经表明，在啮齿动物模型中，免疫细胞或单个细胞因子的耗尽的子集确实是保护性的反对这些高血压的有害影响。但是目前尚无免疫调节疗法高血压，影响全球近50％的成年人。这样做的主要原因是免疫抑制疗法将使很大一部分患者容易感染和恶性肿瘤。最后一个常见实验和人类高血压中免疫激活的途径是T细胞子集的偏向促炎性T助手17（Th17）细胞，分泌白介素17a（IL-17a）和IL-21，并远离抗抗 - 炎性调节T细胞（TREG）。有新的证据表明Rho相关蛋白激酶2 （Rock2）通过促进Th17的分化来充当T辅助细胞中的分子转换，通过磷酸化 STAT3和IRF4，并抑制Treg分化。在此提案中，我们将检验以下新假设高血压与T细胞中Rock2/Stat3/IRF4途径的激活有关，从而导致增加 Th17/Treg比率和加剧的高血压和炎症损伤。此外，我们建议有选择地抑制Rock2将恢复稳态T细胞平衡而不会引起全局免疫抑制。一种新颖的口服生物可用选择性岩石2抑制剂KD025已完成2/3阶段 IL-17A/IL-21介导的自身免疫性疾病的临床试验具有良好的安全性，没有明显的安全性增加感染的风险。我们有新的初步数据可显着降低BP并增加肾脏中的Treg/Th17细胞比响应实验性高血压。在本提案的目标1中，我们将使用诱导的条件岩石2缺乏小鼠来确定岩石2在高血压中的细胞特异性作用。到确定T Cell Rock2删除是否恢复高血压的Th17/Treg平衡在其他细胞类型上，我们将使用一种新型的单细胞技术（称为Cite-Seq）来循环白细胞以及使用全身性脂多糖（LPS）模型对免疫功能进行免疫功能的功能测定炎。在AIM 2中，我们将确定KD025对BP，Th17/Treg余额，最终器官损坏的影响，和LPS引起的炎症响应高血压刺激。在AIM 3中，我们将使用外周血T细胞从正常的和高血压的人类来确定T细胞岩石2活性是否增加高血压。为了确定因果关系，我们将通过人类从人体中传递T细胞为免疫缺陷小鼠确定人类T细胞是否促进岩石中的高血压和肾脏/血管炎症人性化小鼠的依赖方式。我们的团队独特地准备进行这些翻译研究将有可能改变免疫调节疗法，以使其高血压及其相关并发症。