AT2 Receptors in Cardiovascular Control

性状（由申请人提供）：血管紧张素II（Ang II）I型（AT 1） 受体拮抗剂是最新加入的药物 治疗高血压和相关的心血管疾病。虽然这些 药物也引起循环血管紧张素II的大量增加， 临床试验表明，没有严重的副作用与提高水平 这种荷尔蒙。事实上，最近的研究表明，这种AT受体 拮抗剂诱导的血浆Ang II升高可能通过其 血管紧张素Ⅱ 2型（AT 2）受体介导的血管舒张作用。的确，吉恩 “敲除”研究表明，缺乏AT 2受体的突变小鼠表现出 增加基础血压和对Ang II的升压反应。我们用了一本小说 通过体内基因转移技术“敲低”AT 2 R的方法， 支持这一观点。基于这一点以及AT 2受体是 在新生儿AT 2受体的表达中占主导地位，我们已经开发了 根据关于AT 2受体在心血管疾病中的作用的假设， 调控我们认为，在新生大鼠中，AT 2受体参与了 心血管系统的正常发展，并允许它在 生命中的生理界限我们进一步建议，这包括 血管舒张平衡AT 1受体介导的升压作用， 因此，用AT 2 R-AS“敲低”新生儿生命中的AT 2受体， 允许血管收缩机制占主导地位，导致基础血管收缩增加， 血压（BP）和升压反应。相反，在 AT 2受体在新生儿中的表达与AT 2 R-5将允许 血管扩张机制占主导地位，导致升压反应降低 在成年人中。最后，我们提出，血压可以降低自发性高血压大鼠超过 AT 2受体5在新生儿期的表达。我们将检验这些假设 使用分子的、体外的和体内的生理学的组合， 方法，围绕AT 2 R-AS和AT 2受体的逆转录病毒递送 正义（AT 2 R-S）的年轻大鼠，引发对AT 2受体的最大影响。的 具体目标如下：目标1：确定 AT 2受体功能的体外调节。目标2：定义 AT 2受体在心血管系统中的生理作用， 利用AT 2 R-AS在年轻大鼠中的全身递送。目标3：调查 年轻大鼠中AT受体的过度表达是否减弱了 高血压的发展。该提案在方法上具有创新性，因为 它将首次允许对联合国系统的职能进行深入分析， AT 2受体在相对正常的环境中，没有生殖系操纵。我们 我认为这些研究的风险很低，对以下方面的影响很大： 基于基因靶向的新策略的开发，用于治疗 高血压和心血管疾病。

DESCRIPTION (provided by the applicant): Angiotensin II (Ang II) type I (AT1) receptor antagonists are the most recent addition to the arsenal of drugs used n treating hypertension and associated cardiovascular disease. Although these pharmaceutical agents also elicit large increases in circulating Ang II, clinical trials indicate no serious side effects associated with raised levels of this hormone. In fact, recent studies have suggested that this AT, receptor antagonist-induced increase in plasma Ang II may be cardioprotective via its vasodilatory actions mediated by Ang II type 2 (AT2) receptor. Indeed, gene "knockout' studies indicate that mutant mice lacking the AT2 receptor exhibit increased basal BP and pressor responses to Ang II. We have used a novel approach to "knockdown" AT2R by in vivo gene transfer technology to further support this view. Based upon this and the fact that AT2 receptors are predominant in neonatal expression of AT2 receptors, we have developed the following hypotheses concerning the roles of AT2 receptors in cardiovascular regulation. We propose that in neonatal rats AT2 receptors participate in normal development of the cardiovascular system and allow it to operate within physiological boundaries throughout life. WE further propose that this includes a vasodilatory counterbalance to the AT1 receptor-mediated pressor actions of Ang II, Thus, "knocking down" AT2 receptors in neonatal life with AT2R-AS would allow vasoconstrictor mechanisms to predominate, resulting in increased basal blood pressure (BP) and pressor responses in adults. Conversely, over expression of AT2 receptors in neonatal life with AT2R-5 would allow vasodilator mechanisms to predominate, resulting in decreased pressor responses in adults. Finally, we propose that BP can be lowered in SHR rats by over expression of AT2 receptor5 in neonatal life. We will test these hypotheses using a combination of molecular, in vitro and in vivo physiological approaches, centered around the retroviral delivery of AT2R-AS and AT2 receptor sense (AT2R-S) into young rats to elicit maximal effects on AT2 receptors. The specific aims are as follows: Aim 1: To determine the optimal conditions for modulation of AT2 receptor function in vitro. Aim 2: To define the physiological role of the AT2 receptor in the cardiovascular system by utilizing systemic delivery of AT2R-AS in the young rat. Aim 3: To investigate whether over expression of AT; receptors in young rats attenuates the development of hypertension. The proposal is innovative in its approach because it will allow, for the first time, an in depth analysis of the functions of the AT2 receptor in a relatively normal setting, without germ line manipulation. We believe that the studies are low risk in nature and will have a high impact on the development of new strategies based on gene targeting, for the treatment of hypertension and cardiovascular disease.