P7: BRAIN-TARGETED ACE2 OVEREXPRESSION AND BLOOD PRESSURE REGULATION

P7：针对大脑的 ACE2 过度表达和血压调节

• 批准号: 7959748
• 负责人: ERIC D LAZARTIGUES
• 金额: $ 5.55万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959748
• 关键词: Address; Affect; Angiotensin II; Arts; Biology; Brain; Buffers; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Chronic; Computer Retrieval of Information on Scientific Projects Database; Conscious; Development; Disease; Down-Regulation; Elements; Face; Funding; Gene Targeting; Generations; Genes; Genetically Engineered Mouse; Genomics; Grant; Health; Heart; Hypertension; Institution; Kidney; Lead; Mentors; Modeling; Mus; Organ; Peptides; Peptidyl-Dipeptidase A; Physiological; Proteins; Regulation; Regulatory Pathway; Renal function; Renin-Angiotensin System; Research; Research Personnel; Resources; Role; Science; Signal Pathway; Source; System; Therapeutic; Tissues; Transgenes; United States National Institutes of Health; adenovirus mediated delivery; blood pressure regulation; hypertension treatment; in vivo; member; novel therapeutics; overexpression; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The renin-angiotensin system (RAS) is a major regulation of cardiovascular (CV) and renal function in health and disease. The common assumption was that angiotensin-II (ANG-II) served as the main actor of this system. A new member of the RAS, ACE2 (angiotensin converting enzyme type 2) has been identified in organs and tissues related to CV function (e.g. heart, kidney, vessels) and appears to be part of a counter-regulatory pathway buffering the excess of Ang-II. We recently identified the ACE2 protein in the brain in regions involved in the central regulation of blood pressure and showed that it was regulated by other components of the RAS. These observations added to the role of ACE2 in the generation of biologically active peptides supply a rationale for further explorations in the brain in the face of normal and pathophysiological states. In this proposal, we hypothesize that ACE2 is a functional element of the brain in RAS and its down-regulation leads to the development of hypertension. Taking advantage of our expertise in physiological genomics, a science that studies the physiological consequences of gene manipulation, combined to state of the art recording and analysis of CV function and conscious mice, we propose to investigate the effects of transient and chronic ACE2 overexpression on the central regulation of blood pressure and the development of hypertension. Using genetically-engineered mice with brain-targeted ACE2 overexpression and adenovirus-mediated delivery of an ACE2 transgene, we will address the following questions: 1) What are the functional consequences of overexpression of ACE2 in the brain of normal mice? 2) Does chronic ACE2 overexpression in mouse brain prevent or delay the development of hypertension? 3) Does ACE2 overexpression affect Ang-II signaling pathways? We believe that these unique models and gene-targeting approaches will allow us to determine the physiological role of central ACE2 in vivo in hypertension. Evidence of a role of ACE2 in hypertension could lead to the development of new therapeutics as well as a better utilization of existing therapeutics for the treatment of hypertension and other CV diseases.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 肾素-血管紧张素系统（RAS）是健康和疾病中心血管（CV）和肾功能的主要调节因子。 人们普遍认为血管紧张素-II (ANG-II) 是该系统的主要参与者。 RAS 的新成员 ACE2（血管紧张素转换酶 2 型）已在与 CV 功能相关的器官和组织（例如心脏、肾脏、血管）中被发现，并且似乎是缓冲过量 Ang 的反调节途径的一部分-II。 我们最近在大脑中参与血压中枢调节的区域中发现了 ACE2 蛋白，并表明它受到 RAS 的其他成分的调节。 这些观察结果增加了 ACE2 在生物活性肽生成中的作用，为进一步探索大脑面对正常和病理生理状态提供了理论基础。 在此提议中，我们假设 ACE2 是 RAS 中大脑的功能元件，其下调会导致高血压的发生。 利用我们在生理基因组学（一门研究基因操作生理后果的科学）方面的专业知识，结合最先进的对 CV 功能和有意识小鼠的记录和分析，我们建议研究短暂和慢性 ACE2 过度表达对血压的中枢调节和高血压的发展。 使用脑靶向 ACE2 过表达和腺病毒介导的 ACE2 转基因传递的基因工程小鼠，我们将解决以下问题： 1) 正常小鼠大脑中 ACE2 过度表达会产生哪些功能后果？ 2) 小鼠大脑中长期过度表达ACE2是否可以预防或延缓高血压的发生？ 3) ACE2过表达是否影响Ang-II信号通路？ 我们相信，这些独特的模型和基因靶向方法将使我们能够确定中枢 ACE2 在体内高血压中的生理作用。 ACE2 在高血压中的作用的证据可能会导致新疗法的开发以及更好地利用现有疗法来治疗高血压和其他心血管疾病。