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

大脑蛋白质组网络分析阐明阿尔茨海默病的机制和生物标志物

• 批准号: 10403571
• 负责人: Erik C.B. Johnson
• 金额: $ 15.24万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403571
• 关键词: AD transgenic mice; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease test; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Disease Models; Animal Model; Area; Astrocytes; Biochemistry; Bioinformatics; Biological; Biological Markers; Biology; Brain; Brain Diseases; Brain region; Cerebrospinal Fluid; Clinical; Comparative Study; Data Analyses; Diagnosis; Diagnostic tests; Disease; Doctor of Medicine; Doctor of Philosophy; Early Onset Alzheimer Disease; Future; Genetic; Goals; Hippocampus (Brain); Homeostasis; Human; Knowledge; Label; Late Onset Alzheimer Disease; Lead; Life Expectancy; Liquid substance; Mass Spectrum Analysis; Measures; Mentors; Metabolism; Modeling; Molecular; Molecular Biology; Mouse Protein; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurology; Outcome; Pathologic; Pathway Analysis; Persons; Physicians; Population; Prefrontal Cortex; Process; Prognosis; Protein Analysis; Proteins; Proteome; Proteomics; Public Health; Research; Research Project Grants; Research Proposals; Research Technics; Scientist; Systems Biology; Techniques; Testing; Training; United States; age related neurodegeneration; autosomal dominant Alzheimer' s disease; autosomal dominant mutation; base; biomarker discovery; brain tissue; career development; case control; data acquisition; design; differential expression; disorder subtype; early onset; effective therapy; experimental study; frontal lobe; human disease; improved; insight; medical specialties; molecular marker; mouse model; multidisciplinary; neuropathology; novel strategies; preclinical study; presenilin; preservation; programs; protein aggregation; protein biomarkers; protein expression; tau Proteins; tau dysfunction; therapeutic target; therapy development; translational potential; translational study

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.

项目概要 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 由于人类预期寿命的延长，AD 的人口负担正在迅速增加， 不幸的是，导致 AD 的生物机制现在正成为一个紧迫的公共卫生问题。 尚未得到很好的理解，并且针对该疾病的病理特征的疗法尚未被开发出来 迄今为止有效的 AD 疗法的设计和测试困难的原因之一是其转化方面。 进行临床前研究的动物模型尚未明确定义。 目前缺乏用于诊断、预后和治疗靶点参与的良好疾病生物标志物。 研究计划旨在进一步了解 AD 动物模型的转化方面，其目标是 改进模型，并进一步寻求我们对 AD 中发生的病理变化的理解 大脑的目标是开发更好的疾病生物标志物。 AD 大脑的蛋白质组网络分析使人们对复杂的生物学变化有了深入的了解。 发生在阿尔茨海默氏病的蛋白质水平上。 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 到人类疾病，以评估该模型的转化方面（目标 1）。 蛋白质组网络中常染色体显性、散发性早发性和散发性晚发性 AD 相互影响 水平以确定这些形式的 AD 之间的相似性和差异（目标 2）。 大脑中的蛋白质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，以评估它们的效用 AD 生物标志物（目标 3）。这些实验将进一步了解 AD 小鼠之间的关系。 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 β 淀粉样蛋白和 tau 蛋白以外的生物标志物。 我是一名医师科学家，坚定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来增进我们对这种毁灭性衰老疾病的理解 我通过之前的研究和临床接受了多学科培训。 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 神经病学和阿尔茨海默病等神经退行性疾病的亚专业培训这指导了职业生涯。 发展提案旨在扩展这种培训，以发展新的尖端技术的专业知识， 包括强大的蛋白质组学和网络生物学方法，使我可以成为这个新领域的领导者 AD 研究。