Role of endothelin in hypertension-mediated inflammation and end-organ damage

内皮素在高血压介导的炎症和终末器官损伤中的作用

基本信息

批准号：
10579998
负责人：
Carmen De Miguel
金额：
$ 15.26万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10579998
关键词：
Advisory Committees Albumins Applications Grants Autoimmune Diseases Award Basic Science Cardiovascular Diseases Cell Differentiation process Chronic Disease Consumption Development Disease Economic Burden Endothelin Endothelin A Receptor Endothelin-1 Endothelium Excretory function Fibrosis Functional disorder Goals Health Health system Histologic Human Hypertension Immune system Immunology In Vitro Individual Inflammation Inflammatory Intake Investigation Kidney Kidney Diseases Knock-out Knockout Mice Knowledge Link Mediating Mentored Research Scientist Development Award Mentors Modeling Molecular Mus Organ Pathway interactions Peptides Phenotype Physiological Physiology Play Production Proteins Rattus Receptor Activation Renal Hypertension Renal Tissue Reporting Research Research Personnel Risk Role Scheme Sodium Sodium Chloride Sodium-Restricted Diet Source Surface System T cell differentiation T cell infiltration T-Cell Activation T-Lymphocyte TNF gene Testing Training Translating Transplantation Vascular Endothelial Cell Vascular Endothelium blood pressure elevation cardiovascular disorder risk career career development comparison control cytokine dietary dietary salt glomerulosclerosis high salt diet improved in vivo interest interstitial kidney cortex nephrogenesis novel organ injury programs receptor receptor expression receptor function renal damage salt intake salt sensitive hypertension urinary

项目摘要

PROJECT SUMMARY Extensive evidence demonstrates that individuals that regularly consume high salt diet have a greater risk of developing cardiovascular diseases (CVD) compared to individuals on low salt diet. Moreover, dietary consumption of high salt and the associated inflammation have critical roles in the development of CVD, such as hypertension. Particularly, T cells are intimately linked to the development of hypertension. However there is a gap in our knowledge of the mechanisms involved in salt-mediated T cell activation, end-organ damage and CVD risk. Levels of endothelin-1 (ET-1), a potent vasoactive peptide, are elevated after high salt consumption. Renal inflammation is one of the hallmarks of salt-sensitive hypertension, and ET-1 is known to exert pro-inflammatory actions in renal tissue. In fact, human T cells express ET-1 receptors (ETA and ETB) on their surface and are activated by ET-1 in vitro. Recent reports demonstrate that high salt induces production of pro-inflammatory cytokines by T cells. Despite the many studies demonstrating that the renal ET-1 system is an important contributor to increased blood pressure, inflammation and kidney damage during high sodium intake, the molecular mechanisms by which ET-1 mediates these effects remain obscure. Further, the involvement of ET-1 in renal T cell activation and target organ damage during salt-dependent hypertension needs investigation. High salt consumption increases ET-1 production by several cellular sources in the kidney, although the cellular source of ET-1 mediating renal T cell activation and differentiation during high salt remains unclear. This proposal aims to elucidate novel molecular pathways involved in the control of the renal pathophysiology associated with increased blood pressure. This proposal will test that 1) activation of the ET-1/ETA axis leads to kidney T cell activation during salt-sensitive hypertension and results in salt-induced kidney damage and CVD risk, and 2) elevated vascular endothelium-derived ET-1 is responsible for the kidney damage observed during high salt consumption. With the help of my mentor and scientific advisory team, I will continue on the path toward my long-term goal of developing a strong and independent research program at the intersection of immunology and cardio-renal physiology, with the ultimate goal of translating this knowledge to improve human health. If awarded, this K01 award will help me to achieve extra training to become a successful basic science investigator in the field of cardio-renal physiology.

项目概要大量证据表明，经常食用高盐饮食的人患癌症的风险更大与低盐饮食的人相比，更容易患心血管疾病（CVD）。此外，饮食高盐摄入和相关炎症在 CVD 的发展中起着关键作用，例如如高血压。特别是，T细胞与高血压的发生密切相关。然而有我们对盐介导的 T 细胞激活、终末器官损伤和心血管疾病风险。内皮素-1 (ET-1) 是一种有效的血管活性肽，高盐摄入后，内皮素-1 (ET-1) 的水平会升高。肾炎症是盐敏感性高血压的标志之一，已知 ET-1 具有促炎作用在肾组织中的作用。事实上，人类 T 细胞在其表面表达 ET-1 受体（ETA 和 ETB），并且体外被 ET-1 激活。最近的报告表明，高盐会诱导促炎物质的产生 T 细胞产生细胞因子。尽管许多研究表明肾脏 ET-1 系统是重要的高钠摄入期间导致血压升高、炎症和肾脏损伤 ET-1 介导这些作用的分子机制仍不清楚。此外，ET-1的参与盐依赖性高血压期间肾 T 细胞激活和靶器官损伤的影响需要研究。高盐消耗会增加肾脏中多种细胞来源的 ET-1 产量，尽管细胞高盐期间介导肾 T 细胞活化和分化的 ET-1 来源仍不清楚。该提案旨在阐明参与控制肾脏病理生理学的新分子途径与血压升高有关。该提案将测试 1) ET-1/ETA 轴的激活导致盐敏感性高血压期间肾 T 细胞激活并导致盐诱导的肾损伤和 CVD 风险，以及 2) 血管内皮衍生的 ET-1 升高是导致观察到的肾损伤的原因高盐消耗。在我的导师和科学顾问团队的帮助下，我将继续朝着我的长期目标迈进在免疫学和心肾交叉领域开发强大且独立的研究项目生理学，最终目标是将这些知识转化为改善人类健康。如果获奖，这K01 该奖项将帮助我获得额外的培训，成为一名成功的基础科学研究人员心肾生理学。