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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：
8077669
负责人：
Robert Charles Speth
金额：
$ 4.61万
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/8077669
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.

项目概要/摘要大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，人们普遍认为脑血管紧张素会导致高血压和其他心血管疾病。失调。随着对血管紧张素 II 肽片段功能性的认识，一些肽片段具有自己的功能受体，现在已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。我们最近在大脑中发现了一个非 AT1、非 AT2 结合位点这可能会给大脑血管紧张素系统增加一层额外的复杂性。它的存在量较高比主要的血管紧张素受体亚型中的任何一个都可以发挥作用，并且可以作为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。为了更好地理解这个结合位点，该项目针对进一步表征了血管紧张素肽的这种新型脑特异性非 AT1、非 AT2 结合位点。这第一个具体目标是通过聚丙烯酰胺凝胶纯化和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。第二个具体目的是确定其药理学特异性，以确定该结合位点是否具有特异性血管紧张素肽或它是否具有更广泛的底物/配体特异性。第三个具体目标将研究大脑中结合位点的分布，并确定是否与大脑改变相关的条件血管紧张素系统对心血管系统或病理生理状况的调节，例如大脑缺血，如中风、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受体，可以改变特定大脑区域中该结合位点的表达。这些变化应该使我们能够对其可能参与的生理和功能进行功能性神经解剖学评估病理生理情况。预计这种蛋白质将被证明具有相当重要的意义大脑血管紧张素系统的功能。由于大脑血管紧张素系统因引起心血管疾病，这项研究可能会导致开发新的治疗策略治疗高血压和中风。然而，该结合位点在高浓度下出现大脑区域，例如迈纳特基底核、黑质、杏仁核、伏隔核和脊髓的胶质质可以解释大脑血管紧张素的参与阿尔茨海默病和帕金森病、压力和焦虑症、药物滥用和慢性疼痛的系统。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preliminary biochemical characterization of the novel, non-AT1, non-AT2 angiotensin binding site from the rat brain.

DOI：
10.1007/s12020-010-9328-2
发表时间：
2010-06
期刊：
ENDOCRINE
影响因子：
3.7
作者：
Karamyan, Vardan T.;Arsenault, Jason;Escher, Emanuel;Speth, Robert C.
通讯作者：
Speth, Robert C.

Identification of membrane-bound variant of metalloendopeptidase neurolysin (EC 3.4.24.16) as the non-angiotensin type 1 (non-AT1), non-AT2 angiotensin binding site.

金属内肽酶神经溶素 (EC 3.4.24.16) 的膜结合变体鉴定为非血管紧张素 1 型（非 AT1）、非 AT2 血管紧张素结合位点。

DOI：
10.1074/jbc.m111.273052
发表时间：
2012
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Wangler,NaomiJ;Santos,KiraL;Schadock,Ines;Hagen,FredK;Escher,Emanuel;Bader,Michael;Speth,RobertC;Karamyan,VardanT
通讯作者：
Karamyan,VardanT

Distribution of non-AT1, non-AT2 binding of 125I-sarcosine1, isoleucine8 angiotensin II in neurolysin knockout mouse brains.

DOI：
10.1371/journal.pone.0105762
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Speth RC;Carrera EJ;Bretón C;Linares A;Gonzalez-Reiley L;Swindle JD;Santos KL;Schadock I;Bader M;Karamyan VT
通讯作者：
Karamyan VT

Pharmacological characterization of a novel non-AT1, non-AT2 angiotensin binding site identified as neurolysin.

一种新型非 AT1、非 AT2 血管紧张素结合位点（神经溶素）的药理学特征。