KALLIKREINS AND KININS IN HYPERTENSION

激肽释放酶和激肽在高血压中的作用

• 批准号: 3335406
• 负责人: HARRY S MARGOLIUS
• 金额: $ 22.58万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-02-01 至 1992-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3335406
• 关键词: arginine vasopressin; biological fluid transport; calcium transporting ATPase; cellular pathology; eicosanoids; electrophysiology; familial hypertension; gene expression; homeostasis; ion transport; kallikreins; kidney function; laboratory rat; molecular cloning; radioimmunoassay

The objective is to determine whether tissue kallikreins contribute to the pathology of genetic forms of hypertension in animal models, and ultimately, in man. Important advances in knowledge about tissue kallikreins, their gene families, synthesis and regulation, localization and functional responsibilities, and abnormality in hypertensive states were made over the last five years. The role of tissue kallikreins and their kinin products in renal and intestinal ion and water transport is being revealed, especially in regard to calcium-dependent electrogenic chloride secretion and ADH-stimulated water flow. Components of tissue kallikrein-kinin system(s) are present in the brain and show responses to stimuli important to cardiovascular homeostasis. The demonstration of kallikrein-like enzyme(s) in the vascular wall presents a new opportunity for study of a system suggested to have a role in regulation of vascular resistance. We will use new tools to explore regulation, levels of activity, and roles of tissue kallikreins and their products in the above-mentioned sites in spontaneously hypertensive or Dahl rats. They include: kallikrein mRNA, synthesis rate, zymogen, and active enzyme measurements; the ability to develop and/or maintain primary cell cultures which either contain or are responsive to kallikrein system components; the ability to measure other system components (e.g., kinins, kininogen, a new tissue kallikrein binding protein) or biophysical and biochemical responses to such components (e.g., ion fluxes, channel behavior via patch clamping, eicosanoid synthesis or phosphoinositide turnover); monoclonal antibodies to tissue kallikreins which inhibit or stimulate the enzyme; and kinin receptor blockers. Our specific aims are: 1) to compare tissue kallikrein systems in genetic hypertensive models and their controls; 2) to further explain the roles of tissue kallikreins and kinins in membrane transporting events which relate to cardiovascular homeostasis; 3) to determine whether tissue kallikrein systems contribute causally to genetic forms of hypertensive disease; 4) to pursue these objectives in concert with collaborators who provide different perspectives through work on kallikrein gene expression and enzyme responsibilities, and the role of kallikreins in diabetic renal function.

目的是确定组织激肽释放酶是否有助于 动物模型中高血压遗传形式的病理学，以及 最终，在人身上。 组织知识的重要进展 激肽释放酶，其基因家族，合成和调控，定位 和功能责任以及高血压状态下的异常 是在过去五年中制作的。 组织激肽释放酶的作用和 他们的激肽产品在肾脏和肠道离子和水的运输中是 正在被揭示，特别是在钙依赖性生电方面 氯化物分泌和 ADH 刺激的水流。 组织的成分 激肽释放酶-激肽系统存在于大脑中并对 对心血管稳态很重要的刺激。 的示范 血管壁中的激肽释放酶样酶提供了新的机会 用于研究被认为在血管调节中发挥作用的系统 反抗。 我们将使用新工具来探索监管、活动水平和角色 上述位点的组织激肽释放酶及其产物 自发性高血压或达尔大鼠。 它们包括：激肽释放酶 mRNA、 合成率、酶原和活性酶测量；有能力 开发和/或维持原代细胞培养物，其中包含或 对激肽释放酶系统成分有反应；衡量其他的能力 系统成分（例如激肽、激肽原、一种新的组织激肽释放酶结合 蛋白质）或对此类成分的生物物理和生化反应（例如， 离子通量、通过膜片钳的通道行为、类二十烷酸合成或 磷酸肌醇周转率）；组织激肽释放酶单克隆抗体 抑制或刺激酶；和激肽受体阻滞剂。 我们的具体目标是：1）比较遗传中的组织激肽释放酶系统 高血压模型及其控制； 2）进一步解释角色 组织激肽释放酶和激肽在膜转运事件中的相关性 心血管稳态； 3) 判断组织中有无激肽释放酶 系统导致高血压疾病的遗传形式； 4）到 与提供不同服务的合作者共同追求这些目标 通过研究激肽释放酶基因表达和酶的观点 职责以及激肽释放酶在糖尿病肾功能中的作用。