The effect of AT1R antisense on centrally-mediated responses to angiotension II

描述（由申请人提供）：高血压影响大约5000万美国人，这种疾病的进展显着增加心脏和肾衰竭的风险。高血压的发展被认为部分是由于肾素-血管紧张素系统（RAS）的过度活跃，RAS是一种对调节心血管功能和水矿物质平衡至关重要的内分泌系统。RAS的效应肽血管紧张素II（ANGII）介导对失血、钠消耗和低血压的代偿反应。在外周，ANGII通过与血管上的血管紧张素1型受体（AT 1 R）结合来增强血管收缩并促进Na+重吸收。在脑中，ANGII与室周器官（CVO）中的AT 1 R结合，引发激素释放、交感神经流出以及水和钠消耗增加的变化。虽然关于ANGII对血管反应性和肾Na+处理的影响已知很多，但控制对ANGII的反应的中枢途径仍不清楚。以前的研究使用AT 1 R拮抗剂或脑损伤来检查对ANGII的中枢反应，但这些方法有局限性。损伤研究允许评估脑区域的功能，但缺乏提供有关特定神经元表型的信息的分辨率。相反，药理学操作允许评估神经元表型，但将药物施用限制于离散的脑区域是有问题的。另一种方法是使用反义方法来抑制靶基因在离散脑区域中的表达。施用反义改变了个体脑区域内的特定神经元表型，从而允许评价该离散群体内的神经元的功能。对于所提出的实验，反义将用于抑制特定脑核中AT 1 R的表达，从而允许评价这些受体在介导对循环ANGII的应答中的作用。具体地，将靶向AT 1 R的反义注射到大鼠的特定CVO中。随后，我将研究行为，内分泌和神经反应的治疗，差异增加循环血管紧张素Ⅱ。这些结果将为特定脑区中AT 1 R的功能及其在介导对循环ANGII的反应中所起的作用提供有价值的见解，同时也为未来采用中央遗传操作的研究奠定基础。

DESCRIPTION (provided by applicant): Hypertension affects approximately 50 million Americans and progression of this disease significantly increases risks for heart and renal failure. The development of hypertension is believed to be due, in part, to overactivity of the Renin-Angiotensin-System (RAS), an endocrine system critical for the regulation of cardiovascular function and hydromineral balance. The effector peptide of the RAS, angiotensin II (ANGII), mediates compensatory responses to blood loss, sodium depletion, and hypotension. In the periphery, ANGII elicits vasoconstriction and promotes Na+ reabsorption by binding to angiotensin type 1 receptors (AT1R) on blood vessels. In the brain, ANGII binds to AT1R in circumventricular organs (CVOs) to initiate changes in hormone release, sympathetic outflow, and increased water and sodium consumption. While much is known about the effects of ANGII on vasculature reactivity and renal Na+ handling, the central pathways governing responses to ANGII remain unclear. Previous studies have used AT1R antagonists or brain lesions to examine central responses to ANGII, but these approaches have limitations. Lesion studies allow for the evaluation of the function of brain regions, but lack the resolution to provide information about specific neuronal phenotypes. Conversely, pharmacological manipulations allow evaluation of neuronal phenotypes, but limiting the administration of the drug to discrete brain regions is problematic. An alternative method is to use antisense methodology to inhibit the expression of target genes in discrete brain regions. Administration of antisense alters specific neuronal phenotypes within individual brain regions, thereby allowing evaluation of the function of neurons within this discrete population. For the proposed experiments, antisense will be used to inhibit the expression of the AT1R in specific brain nuclei, thereby allowing evaluation of the role of these receptors in mediating responses to circulating ANGII. Specifically, antisense targeted against the AT1R will be injected into specific CVOs of rats. Subsequently, I will examine behavioral, endocrine, and neural responses to treatments that differentially increase circulating ANGII. The results will provide valuable insight to the function of AT1R within specific brain regions and the role they play in mediating responses to circulating ANGII, while also serving as a foundation for future studies employing central genetic manipulations.