Cerebral Amyloid Angiopathy, Vascular Dysfunction & Ischemic Brain Injury

脑淀粉样血管病、血管功能障碍

• 批准号: 7020566
• 负责人: GREGORY J ZIPFEL
• 金额: $ 15.61万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020566
• 关键词: age difference; amyloid proteins; antiantibody; apolipoprotein E; arterioles; autoradiography; brain circulation; brain injury; cerebral ischemia /hypoxia; cerebrovascular disorders; genetically modified animals; laboratory mouse; laser Doppler flowmetry; pathologic process; vasomotion

DESCRIPTION (provided by applicant): The candidate is an academic neurosurgeon specializing in cerebrovascular surgery whose career goal is to investigate the mechanisms underlying ischemic brain injury and intracerebral hemorrhage, with an emphasis on cerebral amyloid angiopathy (CM). The proposed period of mentored scientific training in the laboratory of Dr. David Holtzman at Washington University will allow the candidate to develop the scientific skills to become an independent investigator. CM, which is commonly noted in older patients and is found in the vast majority of patients with Alzheimer's disease, is increasingly implicated as a contributor to cerebral dysfunction, likely through promotion or exacerbation of ischemic brain injury. The central hypotheses that will be tested during the proposed project are as follows: 1) CAA as well as soluble and/or aggregated amyloid beta peptide (A-beta) cause cerebral arteriolar dysfunction. 2) The resulting arteriolar dysfunction is detrimental to cerebral blood flow (CBF), both at baseline and during conditions where autoregulatory mechanisms are required to maintain appropriate cerebral perfusion (i.e. during increased neural activity or systemic hypotension). 3) CAA-induced arteriolar dysfunction and its effects on CBF lead to exacerbation in ischemic brain injury 4) Strategies that block soluble and/or aggregated A-beta will reduce arteriolar dysfunction, abnormal CBF, and ischemic brain injury. The candidate proposes to test these hypotheses using a unique double transgenic mouse model that produces both mutant amyloid precursor protein and apolipoprotein E4, leading to age-dependent development of almost exclusively CAA. In vivo imaging for the measurement of arteriolar function (i.e. vessel diameter response to vasodilatory agents and hypercapnia) will be performed in CAA-affected vessels and appropriate controls. Quantitative cerebral blood flow measurements, both at baseline and during somatosensory activation (whisker stimulation) and elevation/reduction in mean arterial pressure, will be obtained via 14C iodoantipyrine (lAP)-autoradiography and laser-Doppler flowmetry. Ischemic brain injury will be induced by transient middle cerebral artery occlusion. Interventions will include topical and peripheral administration of anti-A-beta antibodies specific to either soluble or aggregated A-beta to determine the effect of A-beta on CAA-induced arteriolar dysfunction, CBF, and ischemic brain injury. This work may lead to new therapeutic options for patients with CAA, Alzheimer's disease, or both disorders. Relevance to Public Health: Cerebral amyloid angiopathy (CAA) is a common blood vessel disorder in older patient populations and is almost always found in patients with Alzheimer's disease. A growing body of evidence suggests that CAA may increase the likelihood that an older individual might suffer a stroke or develop dementia. Results from the proposed research project may lead to new treatment options for those individuals with CAA, Alzheimer's disease, or both disorders.

描述（由申请人提供）：候选人是一位专门从事脑血管外科的学术神经外科医生，其职业目标是研究缺血性脑损伤和脑内出血的机制，重点是脑淀粉样血管病（CM）。拟议在华盛顿大学 David Holtzman 博士实验室进行的指导性科学培训将使候选人培养成为独立研究者的科学技能。 CM 在老年患者中很常见，并且在绝大多数阿尔茨海默病患者中都有发现，它越来越多地被认为是脑功能障碍的一个促成因素，可能是通过促进或加剧缺血性脑损伤来实现的。在拟议的项目中将测试的中心假设如下：1）CAA以及可溶性和/或聚集的淀粉样β肽（A-β）导致脑小动脉功能障碍。 2）由此产生的小动脉功能障碍对脑血流量（CBF）有害，无论是在基线还是在需要自动调节机制来维持适当的脑灌注的情况下（即在神经活动增加或全身性低血压期间）。 3) CAA 诱导的小动脉功能障碍及其对 CBF 的影响导致缺血性脑损伤加剧。 4) 阻断可溶性和/或聚集的 A-β 的策略将减少小动脉功能障碍、异常 CBF 和缺血性脑损伤。该候选人提议使用一种独特的双转基因小鼠模型来测试这些假设，该模型产生突变淀粉样前体蛋白和载脂蛋白 E4，从而导致几乎完全依赖于年龄的 CAA 的发展。将在受 CAA 影响的血管和适当的对照中进行体内成像，以测量小动脉功能（即血管直径对血管舒张剂和高碳酸血症的反应）。通过 14C 碘安替比林 (lAP) 放射自显影和激光多普勒血流测定，可以在基线和体感激活（胡须刺激）期间以及平均动脉压升高/降低期间进行定量脑血流量测量。短暂的大脑中动脉闭塞会引起缺血性脑损伤。干预措施包括局部和外周施用针对可溶性或聚集的 A-β 的特异性抗 A-β 抗体，以确定 A-β 对 CAA 诱导的小动脉功能障碍、CBF 和缺血性脑损伤的影响。这项工作可能会为患有 CAA、阿尔茨海默病或同时患有这两种疾病的患者带来新的治疗选择。与公共健康的相关性：脑淀粉样血管病 (CAA) 是老年患者群体中常见的血管疾病，几乎总是在阿尔茨海默病患者中发现。越来越多的证据表明，CAA 可能会增加老年人中风或患痴呆症的可能性。拟议的研究项目的结果可能会为患有 CAA、阿尔茨海默病或两种疾病的患者带来新的治疗选择。