Diabetes Mellitus, Brain Aging, and Alzheimer's Disease

描述(申请人提供)：糖尿病和阿尔茨海默氏症 疾病(AD)正在扩大健康问题。最近的证据表明 这些疾病可能是相关的，至少在一些患者中是这样，而糖尿病可能 影响阿尔茨海默病的启动或进展。流行病学和 生化数据提示大脑中特定代谢变化的性质 通过它，这种情况可能会发生。此应用程序中描述的实验将 检验年龄、遗传性对环境的易感性的假设 因子和糖尿病共同增加大脑氧化损伤和 在没有中风的情况下神经变性。建议的具体目标如下 (1)测定大脑氧化损伤、AGE形成、神经退行性变和 实验性糖尿病不同模型脑血管并发症的研究 在幼年和老年啮齿动物中单独以及与年龄相关的模型相结合 对大脑的氧化损伤；(2)确定干预措施是否 抑制氧化应激和/或AGE形成在限制大脑方面有效 氧化损伤、AGE形成、神经变性和脑血管病变 在特定目标下开发的模型中的疾病1；和(3)确定氧化 疑似AD患者脑脊液中tau的修饰 开发用于实验疗法的生物标记物 针对具体目标进行调查。 候选人的直接职业目标是将他的研究领域从 癌症遗传学和生物学对阿尔茨海默病及相关痴呆的研究。 具体地说，候选人将被指导如何分析 脑组织和其他组织中氧化脂质和蛋白质的化学病理学 生物样本。他将运用他对遗传模型的理解 疾病到探索遗传和疾病之间复杂关系的研究 环境因素在大脑氧化损伤产生中的作用。这个 在此应用程序中开发的计划将允许他整合培训 以及到目前为止他所接受的神经病理学训练的经验 现在正致力于成为一个富有创造力、生产力和独立性的 内科医生/科学家专注于年龄相关痴呆的机制 疾病。

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) and Alzheimer's disease (AD) are expanding health problems. Recent evidence suggests that these diseases may be related, at least in some patients, and that DM may influence the initiation or progression of AD. Epidemiological and biochemical data suggest the nature of specific metabolic alterations in brain by which this may occur. The experiments described in this application will test the hypothesis that age, inherited susceptibilities to environmental factors, and DM combine to augment brain oxidative damage and neurodegeneration in the absence of stroke. The Specific Aims proposed are (1) to determine brain oxidative damage, AGE formation, neurodegeneration, and complications of cerebrovascular disease in various models of experimental DM in young and old rodents alone and in combination with models of age-related oxidative damage to brain; (2) to determine whether interventions that suppress oxidative stress and/or AGE formation are effective at limiting brain oxidative damage, AGE formation, neurodegeneration, and cerebrovascuiar disease in models developed in Specific Aim 1; and (3) determine oxidative modifications on tau in cerebrospinal fluid (CSF) of probable AD patients to develop biomarkers for use with experimental therapies such as those investigated in Specific Aim 2. The candidate's immediate career goal is to redirect his area of research from cancer genetics and biology to the study of AD and related dementias. Specifically, the candidate will be instructed in methods of analysis of the chemical pathology of oxidized lipids and proteins in brain tissue and other biological samples. He will apply his understanding of genetic models of disease to studies that explore complex relations between genetic and environmental factors in the generation of oxidative damage to brain. The program developed in this application will allow him to integrate the training and experience he has received to date with the neuropathology training he is now undertaking to become a creative, productive, and independent physician/scientist focused on the mechanisms of age-related dementing illnesses.