Cerebral Amyloid Angiopathy, Vascular Dysfunction & Ischemic Brain Injury

脑淀粉样血管病、血管功能障碍

• 批准号: 7350900
• 负责人: GREGORY J ZIPFEL
• 金额: $ 15.76万
• 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/7350900
• 关键词: Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Antibodies; Attenuated; Autoradiography; Blood Vessels; Brain; Caliber; Cerebral Amyloid Angiopathy; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrum; Condition; Dementia; Development; Disease; Elderly; Elevation; Functional disorder; Goals; Homeostasis; Hypercapnia; Hypotension; Image; Immunoglobulin G; Individual; Infarction; Intervention; Ischemic Brain Injury; Laboratories; Laser-Doppler Flowmetry; Lasers; Lead; Measurement; Measures; Mentors; Middle Cerebral Artery Occlusion; Mus; Neurosurgeon; Patients; Peptide antibodies; Perfusion; Peripheral; Population; Public Health; Regulation; Research Personnel; Research Project Grants; Severities; Stroke; System; Testing; Topical application; Training; Transgenic Organisms; Universities; Vascular Diseases; Vibrissae; Washington; Wild Type Mouse; Work; age related; apolipoprotein E-4; blood flow measurement; career; cerebrovascular; cerebrovascular surgery; day; experience; in vivo; iodoantipyrine; mouse model; mutant; novel therapeutics; older patient; pressure; programs; relating to nervous system; research study; response; skills; somatosensory

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.

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机制， 脑淀粉样血管病（CM）。2010年拟议的科学培训期间 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的 成为一名独立调查员。CM，通常见于老年患者， 在绝大多数阿尔茨海默病患者中， 脑功能障碍，可能通过促进或加重缺血性脑损伤。中央 在拟议项目期间将进行测试的假设如下：1）CAA以及可溶性和/或 聚集的淀粉样β肽（Ap）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 需要自动调节机制来维持适当的脑灌注（即在增加的脑灌注期间 神经活动或全身性低血压）。3)CAA诱导的小动脉功能障碍及其对CBF的影响导致 4）阻断可溶性和/或聚集性Ap的策略将减少缺血性脑损伤的恶化。 小动脉功能障碍，异常CBF和缺血性脑损伤。候选人建议测试这些 使用一种独特的双转基因小鼠模型的假设， 蛋白质和载脂蛋白E4，导致几乎完全CAA的年龄依赖性发展。体内 用于测量小动脉功能的成像（即血管直径对血管舒张剂的反应， 高碳酸血症）将在CAA受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（触须刺激）期间的血流量测量， 平均动脉压的升高/降低，将通过14 C碘安替比林（IAP）放射自显影术获得 和激光多普勒血流仪短暂性大脑中动脉栓塞可引起缺血性脑损伤 闭塞干预措施将包括局部和外周给予特异性抗Ap抗体， 可溶性或聚集的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CAA，阿尔茨海默氏症， 疾病，或两种疾病。 与公共卫生的相关性：脑淀粉样血管病（CAA）是一种常见的血管疾病， 老年患者人群，几乎总是在阿尔茨海默病患者中发现。越来越多 有证据表明，CAA可能会增加老年人中风的可能性， 患上痴呆症拟议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、阿尔茨海默病或这两种疾病的个体。