BRADYKININ RECEPTORS IN HYPERTENSION

高血压中的缓激肽受体

• 批准号: 2750412
• 负责人: JULIE CHAO
• 金额: $ 18.68万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-20 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2750412
• 关键词: antisense nucleic acid; blood pressure; bradykinin; gene expression; genetic transcription; genetically modified animals; kidney function; laboratory mouse; laboratory rabbit; molecular cloning; muscle contraction; neuropeptide receptor; protein structure function; spontaneous hypertensive rat; tissue /cell culture; transfection; transfection /expression vector

The objective of this revised proposal is to elucidate the expression and role of bradykiritin (BK) B2 and B receptors in blood pressure and cardiovascular regulation. Kinins are potent vasodilating peptides that are released from precursor kininogens by kallikreins. Kinins bind to BK receptors and mediate a broad spectrum of biological effects including vasodllation, ion transport, smooth muscle contraction and relaxation, pain and inflammation. There are two types of kinin receptors, B2 and B1 which differ in biological properties and primary structures. This project is based on the hypothesis that the BK receptor plays a role in blood pressure regulation which is supported by our encouraging preliminary results that antisense inhibition of B2 receptors in rats causes an increase of blood pressure while transgenic mice over-expressing human B2 receptors are hypotensive. Since the last submission of this application, we continue to make progress in molecular cloning, expression and locallzation of BK receptors, developed essential biochemical and molecular probes and established technologies which form the basis for the current application. The specific aims of this proposal are: (l) to clone and characterize the BK receptor genes from human and rat, and to create DNA constructs with and without adenoviral vectors for somatic gene delivery and transgenic mouse development, (2) to analyze elements which regulate the BK receptor genes' transcription in a-cell culture system by deletion analysis, site-directed mutagensis, gel retardation and footprinting assays, and in vivo by deletion analysis via direct gene delivery, (3) to analyze the role of BK receptors in central and peripheral regulation of blood pressure by antisense inhibition and by combination gene delivery in normotensive and hypertensive rats, (4) to develop and characterize transgenic mice over-expressing BK receptor genes and to analyze phenotypic alterations such as blood pressure changes, renal function and smooth muscle contraction. The proposed studies could provide fundamental information about the structure, regulation and function of BK receptors in order to facilitate the design of therapeutic agents for treating hypertension, cardiovascular disease and inflammation.

这项修订建议的目的，是澄清 缓激肽（BK）B2和B受体在血压中的作用 和心血管调节。激肽是一种有效的血管舒张肽 由激肽释放酶释放的前体激肽原。 激肽结合 BK受体和介导广泛的生物效应 包括血管舒张、离子转运、平滑肌收缩和 松弛、疼痛和炎症。 有两种类型的激肽 受体，B2和B1，其生物学特性不同， 结构.这个项目是基于这样一个假设，即BK 受体在血压调节中起作用， 通过我们令人鼓舞的初步结果， 大鼠中的受体导致血压升高， 过表达人B2受体的小鼠是肥胖的。以来 自上次提交申请以来，我们继续在以下方面取得进展： BK受体的分子克隆、表达和定位， 开发了必要的生物化学和分子探针， 这些技术构成了当前应用的基础。 的 该建议的具体目标是：（l）克隆和表征BK 从人类和大鼠的受体基因，并创建DNA结构， 有或没有腺病毒载体用于体细胞基因递送， 转基因小鼠的发育，（2）分析调控因子， BK受体基因在细胞培养体系中的转录 缺失分析、定点诱变、凝胶阻滞和 足迹分析，并在体内通过缺失分析，通过直接基因 （3）分析BK受体在中枢神经系统中的作用， 外周调节血压的反义抑制和 在正常血压和高血压大鼠中的组合基因递送，（4） 开发和鉴定过表达BK的转基因小鼠 受体基因，并分析表型改变，如血液 压力变化、肾功能和平滑肌收缩。的 拟议的研究可以提供有关 BK受体的结构、调节和功能，以促进 用于治疗高血压的治疗剂的设计， 心血管疾病和炎症。