Cerebroprotection via viral-mediated gene delivery of angiotensin AT2 receptors

通过病毒介导的血管紧张素 AT2 受体基因传递进行脑保护

• 批准号: 7539416
• 负责人: Adam Peter Mecca
• 金额: $ 3.1万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-16 至 2013-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539416
• 关键词: Adrenergic Receptor; Angiotensin II; Angiotensin II Receptor; Angiotensin II Type 1 Receptor Blockers; Animal Model; Antihypertensive Agents; Brain; Cause of Death; Cerebrovascular Circulation; Cerebrum; Clinical Trials; Corpus striatum structure; Data; Development; Disease; Endothelin-1; Fellowship; Gene Delivery; Gene Transfer; Goals; Hypotension; Infarction; Institutes; Investigation; Ischemic Stroke; Life; Mediating; Middle Cerebral Artery Occlusion; Mission; Molecular; National Research Service Awards; Neurites; Neurologic; Neurons; Peptides; Pharmaceutical Preparations; Play; Public Health; Rattus; Receptor Activation; Receptor Gene; Receptor, Angiotensin, Type 1; Role; Stroke; Symptoms; Testing; Type 2 Angiotensin II Receptor; United States; Viral; Work; base; disability; improved; in vivo; nervous system disorder; novel therapeutics; pre-doctoral; preference; receptor; receptor expression; relating to nervous system; research study; size; small hairpin RNA; therapeutic target

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the United States and a major cause of serious, long-term disability. Understanding the mechanisms that underlie stroke and the development of new therapeutic strategies is of key importance and is the long-term objective of this study. Much experimental evidence points to a beneficial action of angiotensin II type 2 receptors (AT2R) in stroke that is enhanced in the presence of Ang II type 1 receptor (AT1R) blockers (ARBs), drugs that are effective anti-stroke agents. Thus, we have developed the general hypothesis that neuronal over expression of AT2R in the cerebral cortical and striatal regions will provide protection during ischemic stroke. In addition, we hypothesize that the combination of AT2R over expression and ARB administration will provide additional cerebroprotection than either alone. Specifically, we hypothesize that viral-mediated delivery of the AT2R gene and consequent neuronal over expression of AT2R within the cortical and striatal regions will reduce the infarct size and neurological deficits resulting from experimentally induced stroke. We further hypothesize that viral mediated delivery of an AT2R shRNA and consequent reduction in AT2R expression will exacerbate the neurological deficits and increase infarct size. The goal of this proposal is to test these hypotheses, using a combination of gene transfer, molecular, cellular and in vivo experimental approaches. The data from this study will not only help to solidify a cerebroprotective role of AT2R in stroke, but will help to determine whether the over expression of AT2R in the CMS can elicit a beneficial action. The specific aims are: (1) Characterize viral-mediated over expression and reduction of AT2R in rat cerebral cortical and striatal regions. (2)Determine whether viral-mediated neuronal over expression of AT2R elicits cerebroprotection during ischemic stroke and improves the cerebroprotective action of ARBs. (3)Determine whether viralmediated reduction of neuronal AT2R potentiates the neural damage elicited by ischemic stroke and reduces the cerebroprotective action of ARBs. In summary, the experiments proposed here will not only allow us to solidify a cerebroprotective role of AT2R in stroke, but will also allow us to determine whether over expression of AT2R in the CNS can provide a beneficial action alone or in in combination with ARBs. PUBLIC HEALTH RELEVANCE: These studies are relevant to public health as they will help to understand what happens in the brain after a stroke occurs, and may identify a new therapeutic target that would be helpful in reducing stroke symptoms. This is clearly relevant to the mission of the National Institutes of Neurological Disorders and Stroke.

描述（由申请人提供）： 中风是美国第三大死亡原因，也是严重、长期残疾的主要原因。了解卒中的发病机制和开发新的治疗策略至关重要，也是本研究的长期目标。许多实验证据表明，血管紧张素II 2型受体（AT2R）在中风中的有益作用在血管紧张素II 1型受体（AT1R）阻断剂（ARB）的存在下得到增强，ARB是有效的抗中风药物。因此，我们提出了一个普遍的假设，即大脑皮层和纹状体区域神经元AT2R的过度表达将在缺血性卒中期间提供保护。此外，我们假设AT2R过表达和ARB给药的组合将提供比单独使用更好的抗肿瘤保护。具体而言，我们假设病毒介导的AT2R基因的传递和随后的皮质和纹状体区域内的神经元AT2R的过度表达将减少实验诱导的中风导致的梗死面积和神经功能缺损。我们进一步假设病毒介导的AT2R shRNA的递送和随后AT2R表达的减少将加剧神经功能缺损并增加梗死面积。本提案的目的是测试这些假设，使用基因转移，分子，细胞和体内实验方法的组合。这项研究的数据不仅有助于巩固AT2R在中风中的神经保护作用，而且有助于确定CMS中AT2R的过度表达是否可以引起有益的作用。具体目的是：（1）研究病毒介导的大鼠大脑皮质和纹状体AT2R的过度表达和减少。（2）研究病毒介导的神经元AT2R过表达是否具有缺血性脑卒中的保护作用，是否能增强ARB的脑保护作用。（3）确定病毒介导的神经元AT2R的降低是否加强了缺血性中风引起的神经损伤并降低了ARB的神经保护作用。总之，本文提出的实验不仅使我们能够巩固AT2R在中风中的神经保护作用，而且还使我们能够确定AT2R在CNS中的过度表达是否可以单独或与ARB联合提供有益作用。 公共卫生相关性：这些研究与公共卫生有关，因为它们将有助于了解中风发生后大脑中发生的事情，并可能确定一种新的治疗靶点，有助于减少中风症状。这显然与国立神经疾病和中风研究所的使命有关。