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

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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.