Neurofibrillary Tangle-Induced Dementia in AD

候选人（Travis Dunckley）于2000年获得亚利桑那大学分子与细胞生物学博士学位，在遗传学、分子生物学和神经生物学方面有着丰富的研究经验。该候选人具有分子神经生物学和受体生物学方面的专业知识。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病因的兴趣，特别是神经原纤维缠结（NFT）导致阿尔茨海默病（AD）的神经元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。使用微阵列来揭示NFT形成的分子基础将需要具备以下知识：1)基因组学，2)AD, 3)细胞生物学，而候选人在这些领域几乎没有背景知识。拟议的计划将为候选人提供一段时间的指导研究，以获得这三个领域的专业知识。在此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研究事业，重点是神经退行性机制。本研究假设CD47信号通路导致AD患者tau代谢异常、NFT形成、神经元细胞死亡和痴呆。这一假设是通过严格的表达谱产生的，并将通过增加更多的AD病例进行分析，并通过显示正常、非痴呆对照不参与CD47信号级联来验证（Aim 1）。此后，我们建议在mRNA、蛋白和功能水平上验证这一途径（目的2）。重要的是，这些实验将确定许多新的和急需的潜在靶点来治疗阿尔茨海默病。Dietrich Stephan博士（导师）将提供基因组学和微阵列数据功能验证方面的培训。Joseph Rogers博士（联合导师）将提供AD和细胞生物学技术方面的培训。通过持续的合作（Dale Schenk和Michael Hutton），将获得病毒siRNA传递和tau细胞系以及磷酸化测定方面的额外资源和技术。TGen为候选人提供的许多资源，结合导师、共同导师和合作者的强大研究项目，将为候选人提供实现其职业目标所需的全面培训，并有望为与年龄相关的痴呆症的最大原因-阿尔茨海默病提供新的治疗方法。

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.