AT1 Angiotensin Receptors in the Renal Circulation Control Blood Pressure

AT1 血管紧张素受体在肾循环中控制血压

• 批准号: 8635640
• 负责人: Matthew Aaron Sparks
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635640
• 关键词: Adrenal Glands; Affect; Angiotensin I; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antihypertensive Agents; Applications Grants; Area; Attenuated; Award; Biological Preservation; Blood Circulation; Blood Pressure; Blood Vessels; Blood flow; Brain; Cardiovascular system; Cell Lineage; Chronic; Clinical Medicine; Clinical Research; Cre-LoxP; Development; Development Plans; Doctor of Philosophy; Ensure; Epithelial; Epithelial Cells; Equilibrium; Excretory function; Gene Targeting; Genetic; Goals; Health; Heart; Heart Diseases; Human; Hypertension; Hypotension; Immunoblotting; Investigation; K-Series Research Career Programs; Kidney; Kidney Diseases; Laboratories; Lead; Measurement; Measures; Mediating; Medical; Mentors; Mentorship; Mission; Molecular; Molecular Biology; Mus; Natriuresis; Nephrons; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Performance; Peripheral Resistance; Pharmaceutical Preparations; Physiological; Receptor, Angiotensin, Type 1; Renal Blood Flow; Renal Circulation; Renal function; Renin-Angiotensin System; Research; Research Personnel; Resistance; Role; Smooth Muscle Myocytes; Sodium; Stroke; Surveys; Sympathetic Nervous System; Technology; Testing; Therapeutic; Tissues; Training; Transgenic Mice; Transplantation; Vascular Smooth Muscle; Vasoconstrictor Agents; Veterans; Wild Type Mouse; Work; abstracting; attenuation; base; blood pressure regulation; body system; career; career development; cell type; defined contribution; effective therapy; experience; improved; in vivo; innovation; insight; kidney vascular structure; knowledge base; mouse model; novel; pressure; public health relevance; receptor; renal epithelium; response; success; therapeutic target; treatment strategy; urinary; vascular contributions; vasoconstriction

Project Summary/Abstract: This first resubmission application for a VA BLR&D Career Development Award 2 (CDA-2) proposes a thorough investigation into the role of the vasculature in the renal circulation in blood pressure homeostasis and hypertension pathogenesis. I am a clinically trained nephrologist whose long-term goal is to understanding the basic mechanisms of hypertension. This proposal will fulfill the educational objective of the development award by facilitating the expansion of my knowledge base into novel lines of inquiry requiring mentorship in these new areas. The expertise of the mentors assisting in this grant proposal will be essential to the successful completion of both the educational mission of the award as well as the performance of the proposed research plan that spans these areas. Thomas Coffman, MD, my primary mentor, has extensive expertise in hypertension research and the renin-angiotensin system; Steven Crowley, MD, will provide expertise in kidney cross transplantation and early career guidance; Susan Gurley, MD, PhD will provide guidance on conditional gene targeting in mice and assessment of sodium transporters in renal epithelia; Christopher Kontos, MD, will provide expertise in endothelial activity and will provide critical mentorship on balancing careers in clinical medicine and research. Additionally, I will participate in a rigorous career development plan as outlined in this application that will be instrumental in ensuring the successful transition to being an independent researcher. PROJECT SUMMARY: Hypertension is a common chronic medical condition significantly impacting cardiovascular health. Medications used to antagonize the renin-angiotensin system, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers effectively reduce blood pressure and uniquely ameliorate cardiovascular complications. The actions of the renin-angiotensin system to control blood pressure are primarily mediated by the type I (AT1) angiotensin receptor. However, AT1 receptors are expressed in multiple cell types in organ systems involved in blood pressure regulation (for example; the brain, heart, kidney, adrenal gland, and blood vessels) and it is not known which cells lineages and tissue compartments mediate their effects. Our preliminary studies in mice lacking AT1 receptors specifically in smooth muscle cells of the vasculature resulted in reduced basal blood pressure and protection from Ang II- induced hypertension. Unexpectedly, our findings suggest that Angiotensin II causes vasoconstriction in the systemic circulation through a combination of direct actions on smooth muscle cells and activation of the sympathetic nervous system. However, in the renal circulation Angiotensin II acts almost exclusively through AT1 receptors on smooth muscle cells of the vasculature. Based on these preliminary findings, we hypothesize that vascular AT1 receptors contribute to the pathogenesis of hypertension primarily by their actions in resistance vessels within the kidney to reduce peritubular blood flow and decrease urinary excretion of sodium, thereby promoting increased blood pressure. This proposed work is innovative, in that it combines physiological measurements in mice with molecular biology approaches. My approach uses a combination novel transgenic mouse models with kidney cross transplantation to answer fundamental questions about blood pressure homeostasis.

项目摘要/摘要：这是退伍军人管理局BLR&D职业发展的第一次重新提交申请 奖项2(CDA-2)建议对血管系统在肾脏中的作用进行彻底的调查 循环中的血压动态平衡与高血压的发病机制。我是一名受过临床训练的 他的长期目标是了解高血压的基本机制。这 提案将通过促进发展奖的扩大来实现发展奖的教育目标 将我的知识基础转化为需要在这些新领域进行指导的新的调查路线。专业知识 协助这项资助计划的导师对顺利完成两项 该奖项的教育使命以及拟议研究计划的执行情况 这些区域。托马斯·科夫曼，医学博士，我的主要导师，在高血压方面有丰富的专业知识 研究和肾素-血管紧张素系统；史蒂文·克劳利医学博士将提供肾脏交叉研究方面的专业知识 移植和早期职业指导；Susan Gurley，医学博士，博士将提供有条件的指导 小鼠的基因打靶和肾上皮细胞钠转运蛋白的评估 MD，将提供内皮活动方面的专业知识，并将提供平衡方面的关键指导 从事临床医学和研究工作。此外，我还将参加一份严谨的职业生涯 本申请中概述的开发计划将有助于确保成功 向独立研究人员过渡。项目简介：高血压是一种常见的疾病 慢性疾病严重影响心血管健康。用于对抗的药物 肾素-血管紧张素系统，如血管紧张素转换酶抑制剂和血管紧张素 受体阻滞剂有效降低血压并独特地改善心血管 并发症。肾素-血管紧张素系统控制血压的作用主要是 由I型(AT1)血管紧张素受体介导。然而，AT1受体在多种组织中表达。 参与血压调节的器官系统中的细胞类型(例如，脑、心脏、肾脏、 肾上腺和血管)，目前还不知道哪些细胞谱系和组织隔间 调解他们的影响。我们对缺乏AT1受体的小鼠的初步研究 血管的肌细胞导致基础血压的降低和血管紧张素Ⅱ的保护作用。 诱发性高血压。出乎意料的是，我们的发现表明血管紧张素II引起血管收缩 在体循环中通过对平滑肌细胞的直接作用和 激活交感神经系统。然而，在肾脏循环中，血管紧张素II起作用 几乎完全通过血管系统的平滑肌细胞上的AT1受体。基于这些 初步发现，我们假设血管AT1受体参与了血管内皮细胞瘤的发病。 高血压主要是通过它们在肾脏内阻力血管的作用来减少肾小管周围 促进血液循环，减少尿钠排泄，从而促进血压升高。这 提议的工作是创新的，因为它结合了老鼠的生理测量和分子 生物学走近了。我的方法使用了一种新的转基因小鼠和肾脏的组合模型 交叉移植以回答有关血压动态平衡的基本问题。