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: 7844980
• 负责人: Robert Charles Speth
• 金额: $ 17.22万
• 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/7844980
• 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; 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; public health relevance; radiotracer; receptor; salt intake; thimet oligopeptidase; treatment strategy; two-dimensional

DESCRIPTION (provided by applicant): 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 specificity 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. PUBLIC HEALTH RELEVANCE: Cardiovascular disease, especially hypertension, is the leading cause of death (629,000 in 2006) in the US. In addition to causing heart failure and kidney damage, hypertension is the primary cause of strokes, which killed 137,000 Americans in 2006, and leaves many others with severe motor and cognitive impairments. The hormone most commonly associated with cardiovascular morbidity is angiotensin II (Ang II). It is arguably the most potent blood pressure-raising hormone. But in addition, it has pathophysiological effects separate from its ability to cause high blood pressure. It is now known that Ang II is made in the brain and exerts powerful influences on the brain systems that regulate blood pressure. Perhaps half of Ang II's ability to raise blood pressure may occur via its actions in the brain. At least one drug company is investigating drugs that specifically target the brain angiotensin system as a treatment for high blood pressure. However, we still do not know how the brain angiotensin system works. We recently discovered a novel binding site for Ang II that is highly expressed and widely distributed throughout the brain in several species including humans. This proposal aims to determine the structural identity and functionality of this novel angiotensin binding site in the brain to assess its role in mediating or antagonizing the pathophysiological actions of Ang II in the brain.

描述（由申请人提供）：关于脑血管紧张素系统的不确定性及其功能有争议。但是，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。随着血管紧张素II的肽片段功能的识别，有些具有自己的受体，现在众所周知，脑血管紧张素具有多种功能，远远超出了心血管系统的调节。最近，我们在大脑中发现了一个非AT1，非AT2结合位点，可能会为脑血管紧张素系统增加一层复杂性。它的数量比任何主要的血管紧张素受体亚型都更高，并且可以作为血管紧张素的新型受体起作用，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，在血管紧张素肽的代谢中起着至关重要的作用。为了更好地理解这种结合位点，该项目旨在进一步表征这种新型的，脑特异性的非AT1，非AT2结合位点，用于血管紧张素肽。第一个具体目的是通过聚丙烯酰胺凝胶纯化和测序技术来定义其生化特征，以确定结合位点的氨基酸序列和结构。第二个具体目的是确定其药理特异性，以确定该结合位点是否针对血管紧张素肽，或者其具有更广泛的底物/配体特异性。第三个具体目的将研究结合位点在大脑中的分布，并确定与心血管系统的改变改变的脑血管紧张素系统调节是否相关的心血管系统或病理生理状况，例如，脑缺血，中风，遗传或实验性高血压，实验性高血压以及在这种特定脑部中缺乏血管紧张素受体的转换小鼠中是否会改变特定脑部的表达。这些变化应该使我们能够对其可能参与生理和病理生理情况进行功能性神经解剖学评估。预计该蛋白在脑血管紧张素系统的功能中将被证明非常重要。由于脑血管紧张素系统因引起心血管疾病而臭名昭著，因此这项研究可能导致发展新型治疗策略来治疗高血压和中风。然而，这种结合位点在高浓度的大脑区域中发生的发生，例如Meynert的基底核，Nigra，Nigra，Amygdala，Amygdala，Accumbens nucumbens和spinaosa的脊髓明胶，可以解释Alzheimer's和Parkinson的痛苦和焦虑症和pressorc症和焦虑症，脑血管生系统的拟议参与。公共卫生相关性：心血管疾病，尤其是高血压，是美国的主要死亡原因（629,000）。除了造成心力衰竭和肾脏损害外，高血压是中风的主要原因，2006年杀死了137,000名美国人，并使许多其他人遭受严重运动和认知障碍。与心血管发病最常见的激素是血管紧张素II（ANG II）。它可以说是最有效的血压激素。但是此外，它的病理生理影响与引起高血压的能力分开。现在已经知道，ANG II是在大脑中产生的，并对调节血压的大脑系统产生强大的影响。也许ANG II升高血压的能力的一半可能会通过其在大脑中的作用而发生。至少一家药品公司正在研究专门针对脑血管紧张素系统的药物，以治疗高血压。但是，我们仍然不知道脑血管紧张素系统的工作原理。我们最近发现了ANG II的一种新型结合位点，该结合位点在包括人类在内的几种物种中高度表达并广泛分布在整个大脑中。该建议旨在确定大脑中这种新型血管紧张素结合位点的结构认同和功能，以评估其在介导或拮抗Ang II在大脑中的病理生理作用中的作用。