Cerebral Amyloid Angiopathy, Vascular Dysfunction & Ischemic Brain Injury

描述（由申请人提供）：候选人是一名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出血的潜在机制，重点是脑淀粉样血管病（CM）。在华盛顿大学大卫霍尔茨曼博士的实验室进行指导性科学培训的建议时间将使候选人发展成为独立调查员的科学技能。CM通常在老年患者中发现，并且在绝大多数阿尔茨海默病患者中发现，越来越多地被认为是脑功能障碍的贡献者，可能通过促进或加重缺血性脑损伤。在拟议项目期间将检验的中心假设如下：1）CAA以及可溶性和/或聚集的淀粉样β肽（A-β）引起脑小动脉功能障碍。2)所产生的小动脉功能障碍对脑血流（CBF）是有害的，无论是在基线还是在需要自动调节机制来维持适当脑灌注的情况下（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的恶化。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。候选人提出使用独特的双转基因小鼠模型来测试这些假设，该模型产生突变的淀粉样前体蛋白和载脂蛋白E4，导致几乎完全CAA的年龄依赖性发展。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（即血管直径对血管扩张剂和高碳酸血症的反应）。通过14 C碘安替比林（IAP）放射自显影和激光多普勒血流测定法，在基线和体感激活（触须刺激）和平均动脉压升高/降低期间进行定量脑血流量测量。短暂性大脑中动脉闭塞可导致缺血性脑损伤。干预措施包括局部和外周给予可溶性或聚集性A-β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CAA，阿尔茨海默病或两种疾病的患者带来新的治疗选择。与公共卫生的相关性：脑淀粉样血管病（CAA）是老年患者人群中常见的血管疾病，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。从拟议的研究项目的结果可能会导致新的治疗方案，为那些个人与CAA，阿尔茨海默病，或这两种疾病。

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.