Brain Proteomic Network Analysis to Elucidate Mechanisms and Biomarkers for Alzheimer's Disease

项目摘要 阿尔茨海默病（AD）是最常见的与年龄相关的神经退行性疾病，影响数百万人 世界各地的人们。由于人类预期寿命的增加，AD的人口负担正在迅速增加， 现在已经成为一个紧迫的公共卫生问题不幸的是，导致AD的生物机制 还没有得到很好的理解，并且针对疾病病理特征的治疗方法还没有得到充分的研究。 至今有效。难以设计和测试AD疗法的一个原因是， 进行临床前研究的动物模型没有很好地定义。另一个原因是， 目前缺乏用于诊断、预后和治疗靶点接合的良好疾病生物标志物。这 研究计划旨在进一步了解AD动物模型的翻译方面，目标是 并试图进一步了解AD的病理变化 目的是开发更好的疾病生物标志物。 AD大脑的蛋白质组学网络分析已经导致了对复杂的生物学变化的见解， 发生在阿尔茨海默病的蛋白质水平上。在本职业发展建议的研究部分， 我的目标是使用基于质谱的蛋白质组网络分析来比较AD转基因小鼠模型 以评估该模型的翻译方面（目的1）。我也会比较 常染色体显性遗传、散发早发性和散发晚发性AD在蛋白质组网络中相互关联 水平，以确定这些形式的广告之间的相似性和差异（目标2）。这些研究的结果 将用于开发一系列蛋白质，我将在脑脊液中测量这些蛋白质，以评估它们作为 AD生物标志物（目标3）。这些实验将进一步加深我们对AD小鼠 模型和人类疾病，我们对早发性AD的理解，以及我们开发AD分子 淀粉样蛋白和tau蛋白以外的生物标志物。 我是一名医生兼科学家，坚定地致力于成为阿尔茨海默病领域的领导者。 研究谁使用新的方法，以促进我们对这种毁灭性的疾病的老龄化的理解， 中枢神经系统我通过以前的研究和临床接受了多学科培训 活动，包括博士学位。生物化学和分子生物学博士受过专业训练， 神经病学和神经退行性疾病（如AD）的专科培训。这种指导性的职业生涯 发展建议寻求扩大这种培训，以发展新的尖端技术的专门知识， 包括强大的蛋白质组学和网络生物学方法，以便我可能成为这个新领域的领导者 AD研究。

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, and affects millions of people worldwide. The population burden of AD is rapidly growing due to increases in human life expectancy, and is now presenting an urgent public health issue. Unfortunately, the biological mechanisms that cause AD are not well understood, and therapies that have targeted pathological hallmarks of the disease have not been effective to date. One reason it is difficult to design and test therapies for AD is that the translational aspects of animal models on which preclinical studies are performed are not well defined. Another reason is that we currently lack good disease biomarkers for diagnosis, prognosis, and therapeutic target engagement. This research proposal aims to further our understanding of the translational aspects of AD animal models with a goal of improving the models, and seeks to further our understanding of the pathological changes that occur in AD brain with a goal of developing better biomarkers for the disease. Proteomic network analysis of AD brain has led to insights about the complicated biological changes that occur at the protein level in Alzheimer’s disease. In the research component of this career development proposal, I aim to use mass spectrometry-based proteomic network analysis to compare an AD transgenic mouse model to the human disease in order to assess the translational aspects of this model (Aim 1). I will also compare autosomal dominant, sporadic early-onset, and sporadic late-onset AD to one another at the proteomic network level to determine the similarities and differences between these forms of AD (Aim 2). Results from these studies in brain will be used to develop a list of proteins that I will measure in cerebrospinal fluid to assess their utility as AD biomarkers (Aim 3). These experiments will further our understanding of the relationship between AD mouse models and human disease, our understanding of early-onset AD, and our goal of developing AD molecular biomarkers beyond the amyloid-β and tau proteins. I am a physician-scientist with a strong commitment to becoming a leader in the field of Alzheimer’s disease research who uses new approaches to advance our understanding of this devastating disease of the aging central nervous system. I have received multidisciplinary training through previous research and clinical activities, including a Ph.D. in Biochemistry and Molecular Biology, and an M.D. with specialty training in neurology and subspecialty training in neurodegenerative diseases such as AD. This mentored career development proposal seeks to extend this training to develop expertise in new cutting-edge techniques, including powerful proteomic and network biology approaches, so that I may become a leader in this new area of AD research.