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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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/文摘