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Role of Renal Lymphatics in Blood Pressure Regulation

肾淋巴管在血压调节中的作用

基本信息

批准号：
10337228
负责人：
BRETT M MITCHELL
金额：
$ 39.62万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337228
关键词：
Adult Affect Albuminuria American Angiotensin II Animals Attenuated Binding Blood Circulation Blood Pressure Cardiovascular Diseases Cardiovascular system Cell Adhesion Cell Communication Cell Proliferation Cell physiology Cells Cellular biology Chronic Chronic Kidney Failure Coronary Arteriosclerosis Data Development Genes Genetic Goals Health Human Hypertension Immune Immune system Immunosuppression Inbred SHR Rats Infiltration Inflammation Inflammatory Injury Injury to Kidney Intercellular Fluid Kidney Kidney Diseases Liquid substance Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphocyte Mediating Mission Molecular Mus Muscle Cells Myocardial Infarction N,N-dimethylarginine National Heart, Lung, and Blood Institute Patients Persons Pharmacology Play Public Health Publications Quality of life Renal Hypertension Reporting Research Resistance Resolution Role Sodium Chloride Stimulus Stroke Testing Transgenic Mice Tumor-infiltrating immune cells Vascular Endothelial Growth Factor D Vascular Endothelial Growth Factor Receptor-3 blood pressure elevation blood pressure reduction blood pressure regulation combat density high risk hypertensive immune activation improved innovation interstitial lymphatic pump lymphatic vessel mutant mycophenolate mofetil nanoparticle nanoparticle delivery negative affect novel therapeutics overexpression precision medicine prevent response salt sensitive hypertension therapeutic target therapeutically effective tissue injury trafficking

项目摘要

PROJECT SUMMARY/ABSTRACT Almost 1 in 2 Americans will develop hypertension (HTN) while half of these people will develop salt-sensitive hypertension (SSHTN). Precision medicine and novel therapies that combat the cardiovascular and renal complications of HTN and SSHTN are critically needed. The long-term goal is to develop a safe and effective therapeutic that targets renal lymphatic vessels to reduce renal injury and HTN. The objectives of this application are to determine the role that renal lymphatics play in renal immune cell accumulation and inflammation in HTN and whether increasing renal lymphatics can reduce renal injury and blood pressure. HTN is associated with activated immune cell infiltration into the kidney leading to interstitial inflammation and renal injury. The resolution of inflammation involves an increase in lymphatic vessels to clear the interstitial immune cells and fluid, but inadequate lymphatic responses result in persistent inflammation and tissue injury. Accumulation of pro-inflammatory immune cells in the kidney plays a key role in HTN; however, the role of renal lymphatics in HTN is unknown. The central hypotheses are that (1) HTN stimuli (salt, angiotensin II, asymmetric dimethylarginine) cause immune cell activation, infiltration, and inflammation in the kidney which contributes to a compensatory increase in renal lymphatics, (2) HTN stimuli in the renal interstitial fluid directly affects renal lymphatic cell biology and function, and (3) that further augmenting renal lymphatics is sufficient to attenuate renal injury and HTN. Recent publications and preliminary data support these hypotheses. The hypotheses will be tested by 3 specific aims: (Aim 1) Determine how renal lymphatics are affected in HTN and the mechanisms involved; (Aim 2) Determine how HTN stimuli directly impact lymphatic cell biology and function; and (Aim 3) Determine how inducing renal lymphangiogenesis affects renal inflammation and HTN. Various combinations of pharmacologic and genetic perturbations of renal lymphatics in mice as well as the examination of molecular mechanisms in lymphatic cells and isolated vessels will be used. The study will also examine renal lymphatics in humans with and without HTN as well as develop and test a kidney-specific nanoparticle that induces lymphangiogenesis. The innovation of the proposed research lies in the elucidation of the role that lymphatic vessels in the kidney play in renal inflammation and blood pressure regulation and how augmenting renal lymphatics can reduce kidney injury and HTN. Technical innovation includes the development of unique transgenic mice and a kidney-specific lymphangiogenic nanoparticle. This contribution will be significant because the results may provide clinicians with a new strategy to improve kidney health and lower blood pressure in some of the ~148 million adults in the US with HTN.

项目概要/摘要近二分之一的美国人会患上高血压 (HTN)，其中一半人会患上盐敏感症高血压（SSHTN）。对抗心血管和肾脏疾病的精准医学和新疗法 HTN 和 SSHTN 的并发症是迫切需要的。长期目标是开发安全有效的针对肾淋巴管以减少肾损伤和高血压的治疗方法。本次活动的目标应用是确定肾淋巴管在肾免疫细胞积累中所起的作用和 HTN 中的炎症以及增加肾淋巴管是否可以减少肾损伤和血压。 HTN 与激活的免疫细胞浸润到肾脏有关，导致间质炎症和肾病受伤。炎症的消退涉及淋巴管的增加以清除间质免疫细胞和液体，但淋巴反应不足会导致持续的炎症和组织损伤。肾脏中促炎性免疫细胞的积累在高血压中起着关键作用；然而，的作用 HTN 中的肾淋巴管情况尚不清楚。中心假设是 (1) HTN 刺激（盐、血管紧张素 II、不对称二甲基精氨酸）会导致肾脏中的免疫细胞激活、浸润和炎症，有助于肾淋巴管代偿性增加，（2）HTN直接刺激肾间质液影响肾淋巴细胞的生物学和功能，并且（3）进一步增加肾淋巴管足以减轻肾损伤和高血压。最近的出版物和初步数据支持这些假设。这假设将通过 3 个具体目标进行检验：（目标 1）确定肾淋巴管在 HTN 中如何受到影响，所涉及的机制；（目标 2）确定 HTN 刺激如何直接影响淋巴细胞生物学和功能; （目标 3）确定诱导肾淋巴管生成如何影响肾脏炎症和高血压。小鼠肾淋巴管的药理学和遗传扰动的各种组合以及将使用淋巴细胞和分离血管的分子机制检查。该研究还将检查有或没有 HTN 的人的肾淋巴管，并开发和测试肾脏特异性诱导淋巴管生成的纳米颗粒。本研究的创新之处在于阐明了肾脏淋巴管在肾脏炎症和血压调节中的作用增强肾淋巴管如何减少肾损伤和高血压。技术创新包括开发独特的转基因小鼠和肾脏特异性淋巴管生成纳米颗粒。这个贡献意义重大，因为研究结果可能为临床医生提供改善肾脏健康的新策略降低美国约 1.48 亿患有高血压的成年人中部分人的血压。