Diabetes Mellitus, Brain Aging, and Alzheimer's Disease

描述（由申请人提供）：糖尿病（DM）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如此， 影响AD的发生或进展。流行病学和 生化数据表明，大脑中特定的代谢改变的性质 这可能会发生。本申请中描述的实验将 检验年龄、遗传对环境的敏感性 因子和DM联合收割机增加脑氧化损伤， 在没有中风的情况下发生神经变性。建议的具体目标是 (1)以确定脑氧化损伤、AGE形成、神经变性和 不同实验性糖尿病模型脑血管病并发症 在单独的年轻和老年啮齿动物中以及与年龄相关的模型组合中， 氧化损伤脑;（2）以确定是否干预， 抑制氧化应激和/或AGE形成可有效限制脑 氧化损伤、AGE形成、神经退行性变和血管紧张素转换酶 在特定目标1中开发的模型中的疾病;以及（3）确定氧化 可能的AD患者的脑脊液（CSF）中tau蛋白的改变， 开发用于实验疗法的生物标志物， 具体目标2。 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AD和相关痴呆症的研究。 具体来说，候选人将在分析方法的指导下， 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， 疾病的研究，探索遗传和 环境因素对脑氧化损伤的产生。的 在这个应用程序中开发的程序将允许他整合培训 和经验，他已经收到了迄今为止的神经病理学培训，他是 现在承诺成为一个创造性的，多产的，独立的 专注于与年龄相关的痴呆机制的医生/科学家 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.