Neurofibrillary Tangle-Induced Dementia in AD

候选人（特拉维斯·邓克利）获得了博士学位。亚利桑那大学的分子和细胞生物学博士， 2000年，并在遗传学，分子生物学和神经生物学方面有着富有成效的研究历史。这位候选人有 分子神经生物学和受体生物学的专业知识。翻译基因组学研究的最新研究成果 研究所（TGen）已经激发了人们对阐明神经退行性疾病病因学的兴趣，特别是， 神经元缠结（NFT）导致神经元细胞死亡和阿尔茨海默氏症痴呆的机制 疾病（AD）。AD是一种复杂的遗传性疾病，特别适合通过表达进行基因组分析。 侧写使用微阵列来揭示NFT形成的分子基础将需要以下知识：1）基因组学， 2)AD，3）细胞生物学，候选人几乎没有背景的领域。拟议的计划将为候选人提供 在一段时间的指导下进行研究，以获得这三个领域的专业知识。在这方面获得的专业知识 指导期将使候选人实现其发展独立，多学科的长期目标 在神经科学的研究生涯，重点是神经退行性机制。在拟议的研究中， 假设CD 47信号通路导致tau代谢、NFT形成和 神经元细胞死亡和痴呆。这一假设是由严格的表达谱产生的， 通过在分析中增加更多的AD病例，并显示正常的非痴呆对照组没有 CD 47信号级联的参与（Aim 1）。此后，我们建议在mRNA上验证这一途径， 蛋白质和功能水平（目标2）。重要的是，这些实验将确定许多新的和急需的 治疗AD的潜在靶点。Dietrich Stephan博士（导师）将提供基因组学培训， 微阵列数据的功能验证。约瑟夫·罗杰斯博士（共同导师）将提供AD和细胞生物学培训 技术.病毒siRNA递送和tau细胞系和磷酸化测定中的其他资源和技术 将通过持续的合作（Dale Schenk和Michael赫顿）获得。的许多资源 提供给候选人在TGen，结合导师，共同导师，和 合作者，将为候选人提供实现其职业目标所需的全面培训， 希望能为老年痴呆症的最大病因--阿尔茨海默病找到新的治疗方法。

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.