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

项目总结 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。由于人类预期寿命的增加，阿尔茨海默病的人口负担正在迅速增加， 现在提出了一个紧迫的公共卫生问题。不幸的是，导致阿尔茨海默病的生物学机制 目前还不清楚，针对该病病理特征的治疗方法也没有得到很好的了解 到目前为止有效。设计和测试AD的治疗方法很困难的一个原因是， 进行临床前研究的动物模型并没有得到很好的定义。另一个原因是我们 目前缺乏良好的疾病生物标志物用于诊断、预后和治疗靶点。这 研究提案旨在加深我们对AD动物模型翻译方面的理解，目的是 改进模型，并试图加深我们对AD病理变化的理解 目的是为这种疾病开发更好的生物标志物。 对AD大脑的蛋白质组网络分析导致了对复杂的生物学变化的洞察 在阿尔茨海默病中发生在蛋白质水平。在这份职业发展提案的研究部分， 我的目标是使用基于质谱学的蛋白质组网络分析来比较AD转基因小鼠模型 以评估这一模式的翻译方面(目标1)。我也会比较一下 在蛋白质组网络中，常染色体显性遗传、散发性早发和散发性晚发AD相互关联 以确定这些形式的AD之间的异同(目标2)。这些研究的结果 将被用来开发一份蛋白质清单，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小鼠之间关系的了解 模型和人类疾病，我们对早发性AD的理解，以及我们开发AD分子的目标 淀粉样蛋白-β和tau蛋白以外的生物标记物。 我是一名内科科学家，坚定地致力于成为阿尔茨海默病领域的领导者 研究人员使用新方法促进我们对这一毁灭性的老龄化疾病的理解 中枢神经系统。我通过以前的研究和临床接受了多学科的培训 活动，包括生物化学和分子生物学博士学位，以及接受过专业培训的医学博士学位 神经学和阿尔茨海默病等神经退行性疾病的专科培训。这个受过指导的职业生涯 发展建议旨在扩大这项培训，以发展新的尖端技术方面的专门知识， 包括强大的蛋白质组学和网络生物学方法，这样我就可能成为这个新领域的领导者 AD研究的专家。

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.