Brain specific non-AT1, non-AT2 angiotensin binding site

项目摘要/摘要 关于脑血管紧张素系统有许多不确定性，其功能也存在争议。 然而，人们普遍认为脑血管紧张素会引起高血压和其他心血管疾病。 精神错乱。随着对血管紧张素II的功能的认识，一些片段有自己的功能 受体，现在已经知道大脑血管紧张素有多种功能，远远超出了 心血管系统的调节。我们最近在大脑中发现了一个非AT1、非AT2结合部位 这可能会给大脑血管紧张素系统增加一层额外的复杂性。它以更高的数量存在 而不是任何一种主要的血管紧张素受体亚型，并且可以作为一种新的受体发挥作用 血管紧张素可能仅限于大脑，也可能是一种高度特异的血管紧张素酶，在 在血管紧张素肽代谢中的作用。为了更好地了解此绑定站点，此项目指向 进一步表征了这一新的脑特异性非AT1、非AT2血管紧张素肽结合位点。这个 第一个具体目标是通过聚丙烯酰胺凝胶纯化和鉴定其生化特性 测序技术来确定结合位点的氨基酸序列和结构。第二 具体目的是确定其药理学特异性，以确定该结合位点是否对 血管紧张素肽或它是否具有更广泛的底物/配体专一性。第三个具体目标是研究 结合部位在大脑中的分布，并确定条件是否与大脑改变有关 血管紧张素系统对心血管系统或病理生理条件的调节，例如大脑 中风、遗传性或实验性高血压以及缺乏血管紧张素的转基因小鼠的缺血 受体，可以改变这个结合部位在特定大脑区域的表达。这些变化应该能让我们 对其可能参与的生理和神经功能进行神经解剖学评估 病理生理环境。预计这种蛋白质将被证明是相当重要的。 脑血管紧张素系统的功能。因为大脑血管紧张素系统是臭名昭著的 心血管疾病，这项研究可能导致开发新的治疗策略 治疗高血压和中风。然而，这一结合位点在高浓度下出现在 大脑区域，如Meynert基底核、黑质、杏仁核、伏隔核和 脊髓的胶状质可以解释脑血管紧张素的参与。 阿尔茨海默氏症和帕金森氏症、压力和焦虑症、药物滥用和慢性疼痛的系统。

Project Summary/Abstract There are many uncertainties about the brain angiotensin system and its functionality is controversial. However, it is generally accepted that brain angiotensin causes hypertension and other cardiovascular disorders. With the recognition of functionality of peptide fragments of angiotensin II some having their own receptors, it is now known that brain angiotensins have a multitude of functions extending well beyond regulation of the cardiovascular system. We recently discovered a non-AT1, non-AT2 binding site in the brain that may add an additional layer of complexity to the brain angiotensin system. It is present in higher quantities than either of the major angiotensin receptor subtypes and could function either as a novel receptor for angiotensins that may be limited to the brain, or it could be a highly specific angiotensinase that plays a critical role in the metabolism of angiotensin peptides. To better understand this binding site, this project is directed to further characterizing this novel, brain-specific non-AT1, non-AT2 binding site for angiotensin peptides. The first specific aim is to define its biochemical characteristics through polyacrylamide gel purification and sequencing techniques to determine the amino acid sequence and structure of the binding site. The second specific aim is to determine its pharmacological specifity to determine if this binding site is specific for angiotensin peptides or if it has a broader substrate/ligand specificity. The third specific aim will study the distribution of the binding site in the brain and ascertain whether conditions associated with altered brain angiotensin system regulation of the cardiovascular system or pathophysiological conditions, e.g., brain ischemia as in stroke, genetic or experimental hypertension and in transgenic mice lacking angiotensin receptors, can alter the expression of this binding site in specific brain regions. The changes should enable us to do a functional neuroanatomical assessment of its possible participation in physiological and pathophysiological circumstances. It is anticipated that this protein will prove to be of considerable importance in the functionality of the brain angiotensin system. Since the brain angiotensin system is notorious for causing cardiovascular disease, this research could lead to the development of novel therapeutic strategies for treatment of hypertension and stroke. However the occurrence of this binding site in high concentrations in brain regions such as the nucleus basalis of Meynert, substantia nigra, amygdala, nucleus accumbens and substantia gelatinosa of the spinal cord could explain the proposed involvement of the brain angiotensins system in Alzheimer's and Parkinson's Disease, stress and anxiety disorders, drug abuse and chronic pain.