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.

项目概要高血压刺激激活先天性和适应性免疫细胞，然后作用于靶器官，例如肾脏和脉管系统导致组织损伤/炎症和高血压终末器官损伤。我们和其他人已经表明，在啮齿动物模型中消除免疫细胞子集或个体细胞因子确实具有保护作用对抗高血压的这些有害影响。但目前尚无免疫调节疗法高血压，影响全球近 50% 的成年人。造成这种情况的一个主要原因是免疫抑制治疗将使很大一部分人容易受到感染和恶性肿瘤。最后一个共同点实验性和人类高血压中免疫激活的途径是 T 细胞亚群偏向于促炎 T 辅助细胞 17 (Th17) 细胞分泌白细胞介素 17A (IL-17A) 和 IL-21，并远离抗炎细胞炎症调节 T 细胞 (Treg)。有新的证据表明 Rho 相关蛋白激酶 2 (ROCK2) 通过磷酸化促进 Th17 分化，充当 T 辅助细胞中的分子开关 STAT3和IRF4，并抑制Treg分化。在这个提案中，我们将测试这个新假设：高血压与 T 细胞中 ROCK2/STAT3/IRF4 通路的激活有关，从而导致 Th17/Treg 比率并加剧高血压和炎症损伤。此外，我们建议选择性抑制 ROCK2 将恢复 T 细胞稳态平衡，而不会导致全局免疫抑制。一种新型口服生物可利用的选择性 ROCK2 抑制剂 KD025 已完成 2/3 期研究 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，并且没有明显的副作用感染风险增加。我们有新的初步数据表明 KD025 显着降低血压并增加血压肾脏中 Treg/Th17 细胞比率对实验性高血压的反应。在本提案的目标 1 中，我们将使用诱导条件 ROCK2 缺陷小鼠来确定 ROCK2 在高血压中的细胞特异性作用。到确定 T 细胞 ROCK2 缺失是否能以最小的影响恢复高血压患者的 Th17/Treg 平衡对于其他细胞类型，我们将使用一种称为 CITE-Seq 的新型单细胞技术来对循环白细胞进行表型分析以及使用全身脂多糖（LPS）模型进行免疫功能的功能测定炎。在目标 2 中，我们将确定 KD025 对血压、Th17/Treg 平衡、终末器官损伤、以及脂多糖（LPS）诱导的对高血压刺激的炎症反应。在目标 3 中，我们将使用外周血 T 细胞从正常血压和高血压人群中检测 T 细胞 ROCK2 活性是否在高血压。为了确定因果关系，我们将把人类的 T 细胞过继转移到免疫缺陷小鼠体内确定 ROCK2 中人类 T 细胞是否会促进高血压和肾脏/血管炎症人源化小鼠中的依赖方式。我们的团队以独特的方式进行这些转化研究可能会改变高血压及其相关并发症的免疫调节疗法。