Neurofibrillary Tangle-Induced Dementia in AD

描述(申请人提供)：候选人特拉维斯·邓克利(Travis Dunckley)2000年在亚利桑那大学获得分子和细胞生物学博士学位，并在遗传学、分子生物学和神经生物学方面拥有丰富的研究历史。该候选人在分子神经生物学和受体生物学方面拥有专业知识。翻译基因组学研究所(TGen)最近的工作激发了人们对阐明神经退行性疾病的病因学的兴趣，特别是神经原纤维缠结(NFT)导致阿尔茨海默病(AD)神经细胞死亡和痴呆的机制。AD是一种复杂的遗传疾病，特别适合通过表达谱进行基因组分析。使用微阵列来发现形成NFT的分子基础将需要以下方面的知识：1)基因组学，2)AD，3)细胞生物学，候选人在这些领域几乎没有背景。拟议的计划将为候选人提供一段时间的指导性研究，以便获得这三个领域的专门知识。在指导期间获得的专业知识将使候选人能够实现他的长期目标，即在神经科学领域发展独立的、多学科的研究生涯，重点是神经退化机制。在拟议的研究中，假设CD47信号通路有助于AD患者tau代谢、NFT形成以及神经细胞死亡和痴呆的异常。这一假设是由严格的表达谱产生的，并将通过将更多的AD病例添加到分析中并通过显示正常的、非痴呆的对照组没有参与CD47信号级联反应(目标1)来验证。此后，我们建议在mRNA、蛋白质和功能水平上验证这一途径(目标2)。重要的是，这些实验将为AD的治疗确定许多新的和迫切需要的潜在靶点。Dietrich Stephan博士(Mentor)将提供基因组学和微阵列数据功能验证方面的培训。约瑟夫·罗杰斯博士(共同导师)将提供AD和细胞生物学技术方面的培训。在病毒siRNA传递和tau细胞系以及磷酸化分析方面的其他资源和技术将通过持续不断的合作获得(Dale Schenk和Michael Hutton)。TGen为候选人提供的众多资源，与导师、共同导师和合作者的强大研究计划相结合，将为候选人提供实现其职业目标所需的全面培训，并有望为老年痴呆症的最大原因-阿尔茨海默病找到新的治疗方法。

DESCRIPTION (provided by applicant): The candidate (Travis Dunckley) received his Ph.D. in Molecular and Cellular Biology from the University of Arizona in 2000, and has a history of productive research in genetics, molecular biology, and neurobiology. The candidate has expertise in molecular neurobiology and receptor biology. Recent work at the Translational Genomics Research Institute (TGen) has stimulated an interest in elucidating the etiology of neurodegenerative diseases, in particular, the mechanisms whereby neurofibrillary tangles (NFT) contribute to the neuronal cell death and dementia of Alzheimer's disease (AD). AD is a complex genetic disorder that is particularly amenable to genomic analysis via expression profiling. Using microarrays to uncover the molecular bases for NFT formation will require knowledge of: 1) genomics, 2) AD, 3) cell biology, areas in which the candidate has little background. The proposed plan will provide the candidate with a period of mentored research in order to gain expertise in these three areas. The expertise gained in this mentoring period will allow the candidate to attain his long-term goal of developing an independent, multidisciplinary research career in neuroscience, with an emphasis on neurodegenerative mechanisms. In the proposed study it is hypothesized that the CD47 signaling pathway contributes to abnormalities in tau metabolism, NFT formation, and neuronal cell death and dementia in AD. This hypothesis has been generated by stringent expression profiles and will be validated by adding more AD cases to the analysis and by showing that normal, non-demented controls have no involvement of the CD47 signaling cascade (Aim 1). Thereafter, we propose to validate this pathway at the mRNA, protein, and functional levels (Aim 2). Importantly, these experiments will identify numerous new and much needed potential targets for the treatment of AD. Dietrich Stephan, Ph.D. (mentor) will provide training in genomics and functional validation of microarray data. Joseph Rogers, Ph.D. (co-mentor) will provide training in AD and cell biological techniques. Additional resources and techniques in viral siRNA delivery and tau cell lines and phosphorylation assays will be received through continued ongoing collaborations (Dale Schenk and Michael Hutton). The many resources available to the candidate at TGen, in combination with the strong research programs of the mentor, co-mentor, and collaborators, will provide the candidate with the comprehensive training necessary to achieve his career goals and, hopefully, arrive at new therapeutic modalities for the largest cause of age-related dementia - Alzheimer's disease.