Cerebral Amyloid Angiopathy, Vascular Dysfunction & Ischemic Brain Injury

候选人是一名专门从事脑血管外科的学术神经外科医生，他的职业目标是 探讨缺血性脑损伤和脑出血的机制 重视脑淀粉样血管病(CM)。拟议的科学辅导式培训期间 华盛顿大学大卫·霍尔茨曼博士的实验室将允许候选人开发科学 成为一名独立调查员的技能。CM，常见于老年患者，常见于 在绝大多数阿尔茨海默病患者中，越来越多的人被认为是 脑功能障碍，可能是通过促进或加重缺血性脑损伤。中环 将在提议的项目期间测试的假设如下：1)CAA以及可溶和/或 聚集性淀粉样β蛋白(AP)可引起脑小动脉功能障碍。2)由此产生的小动脉 功能障碍对脑血流量(CBF)是有害的，无论是在基线还是在以下情况下 需要自动调节机制来维持适当的脑血流灌注(即，在增加 神经活动或全身性低血压)。3)CAA所致小动脉功能障碍及其对脑血流量的影响 缺血性脑损伤的加重4)阻断可溶性和/或聚集AP的策略将减少 小动脉功能障碍、脑血流异常和缺血性脑损伤。候选人建议对这些进行测试 使用独特的双转基因小鼠模型进行假设，该模型产生突变的淀粉样前体 蛋白质和载脂蛋白E4，导致几乎完全依赖于年龄的CAA的发展。活体内 用于测量小动脉功能(即血管直径对血管扩张剂的反应和 高碳酸血症)将在受CAA影响的血管和适当的对照中进行。定量脑 在基线和躯体感觉激活(胡须刺激)和 平均动脉压的升高/降低将通过~(14)C碘安替比林(LAP)放射自显影获得 和激光多普勒血流计。短暂性大脑中动脉将导致缺血性脑损伤 遮挡。干预措施将包括局部和外周注射抗AP特异性抗体 无论是可溶性AP还是聚集性AP，以确定AP对CAA诱导的小动脉功能障碍、CBF、 和缺血性脑损伤。这项工作可能会为阿尔茨海默病患者带来新的治疗选择 疾病或两者兼而有之。 与公众健康相关：脑淀粉样血管病(CAA)是一种常见的血管疾病 老年患者群体，几乎总是在阿尔茨海默病患者中发现。成长中的身体 大量证据表明，CAA可能会增加老年人患中风或 患上痴呆症。拟议的研究项目的结果可能会为这些患者带来新的治疗选择 患有CAA、阿尔茨海默病或两者兼有的个体。

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 (Ap) 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 Ap 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-Ap antibodies specific to either soluble or aggregated Ap to determine the effect of Ap 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.