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

脑特异性非 AT1、非 AT2 血管紧张素结合位点

• 批准号: 8077661
• 负责人: Robert Charles Speth
• 金额: $ 1.56万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077661
• 关键词: AGTR2 gene; Acids; Address; Affect; Affinity; Alzheimer' s Disease; American; Amino Acid Sequence; Amygdaloid structure; Angiotensin II; Angiotensin II Receptor; Angiotensin Receptor; Angiotensin Receptor Binding; Angiotensins; Anxiety Disorders; Basal Nucleus of Meynert; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Preservation; Blood Pressure; Brain; Brain Ischemia; Brain region; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cavia; Cerebrovascular Circulation; Characteristics; Complement; Cysteine; Development; Disease; Drug abuse; Electrolyte Balance; Enzymes; Future; Gel; Gene Expression; Genetic; Heart failure; Hormones; Human; Hypertension; Impaired cognition; Infusion procedures; Kidney; Knock-out; Knowledge; Lead; Left; Ligands; Light; Liquid substance; Liver; Mediating; Membrane; Metabolic; Metabolism; Middle Cerebral Artery Occlusion; Modeling; Morbidity - disease rate; Motor; Movement Disorders; Mus; Nerve Degeneration; Nervous system structure; Neurons; Neuropeptides; Nucleus Accumbens; Oryctolagus cuniculus; Oxidation-Reduction; Parkinson Disease; Peptide Fragments; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Physiological; Play; Predisposition; Proteins; Radiolabeled; Rat Strains; Rattus; Reactive Oxygen Species; Reducing Agents; Regulation; Reporting; Research; Research Infrastructure; Rodent; Role; Site; Specificity; Spinal Cord; Stress; Stroke; Structure; Substantia Gelatinosa; Substantia nigra structure; Sulfhydryl Reagents; Surveys; System; Techniques; Transgenic Mice; Uncertainty; Work; abstracting; angiotensinase; base; blood pressure regulation; chronic pain; crosslink; high throughput screening; hypertension treatment; inhibitor/antagonist; killings; metabolic abnormality assessment; neurolysin; normotensive; novel; novel therapeutics; polyacrylamide gels; radiotracer; receptor; salt intake; thimet oligopeptidase; treatment strategy; two-dimensional

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.

项目总结/摘要 脑血管紧张素系统存在许多不确定性，其功能也存在争议。 然而，普遍认为脑血管紧张素导致高血压和其他心血管疾病， 紊乱随着对血管紧张素II的肽片段的功能性的识别，一些肽片段具有它们自己的功能， 由于血管紧张素受体，现在已知脑血管紧张素具有多种功能， 调节心血管系统。我们最近在大脑中发现了一个非AT 1，非AT 2结合位点， 这可能会给大脑血管紧张素系统增加额外的复杂性。它以更高的量存在 比任何一种主要的血管紧张素受体亚型，可以作为一种新的受体， 血管紧张素可能仅限于大脑，或者它可能是一种高度特异性的血管紧张素酶， 在血管紧张素肽代谢中的作用。为了更好地了解这个绑定网站，这个项目是针对 进一步表征了血管紧张素肽的这种新的脑特异性非AT 1、非AT 2结合位点。的 第一个具体目的是通过聚丙烯酰胺凝胶纯化来确定其生化特性， 测序技术以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特异于 血管紧张素肽或如果它具有更广泛的底物/配体特异性。第三个具体目标将研究 结合位点在脑中的分布，并确定是否与改变的脑 血管紧张素系统调节心血管系统或病理生理状况，例如，大脑 缺血如中风、遗传性或实验性高血压和缺乏血管紧张素Ⅱ的转基因小鼠 受体，可以改变在特定的大脑区域的这种结合位点的表达。这些变化应该能让我们 做一个功能性神经解剖学评估， 病理生理环境。预计这种蛋白质将被证明是相当重要的 大脑血管紧张素系统的功能。因为脑血管紧张素系统是臭名昭著的， 心血管疾病，这项研究可能导致新的治疗策略的发展， 治疗高血压和中风。然而，这种结合位点在高浓度下的出现， 大脑区域，如Meynert基底核、黑质、杏仁核、延髓核和 脊髓胶状质可以解释脑血管紧张素的参与 系统在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。