Changing tau Protein Levels and tau Protein Isoforms in Mouse Models of Dementia

描述（由申请人提供）：Timothy Miller博士，医学博士，是一位训练有素的内科科学家，长期对衰老和神经退行性疾病感兴趣。他最近开始在华盛顿大学担任神经病学助理教授，现在正在寻求进一步指导的支持，因为他专注于阿尔茨海默病和额颞叶痴呆的新治疗策略。基于先前使用反义寡核苷酸下调大脑和脊髓基因的经验，米勒博士现在正在使用类似的策略，通过改变外显子剪接来降低tau蛋白的总体水平或降低4R:3R tau蛋白的比例。他将测试tau蛋白的这些变化是否会影响淀粉样蛋白沉积小鼠或N279K tau突变小鼠的行为和病理表型。他的短期目标是开始学术生涯，扩大一个小型的转化研究小组，获得独立资金（RO1），并获得理解和治疗阿尔茨海默病和额颞叶痴呆小鼠模型的经验。米勒博士的长期目标是建立一个中等规模的、令人兴奋的研究小组，对老年神经退行性疾病的理解和治疗产生真正的影响。为了实现这些目标，他聘请了两位在老龄化研究方面经验丰富的杰出研究人员大卫·霍尔茨曼（David Holtzman）和艾莉森·戈特（Alison Goate）作为导师。他的职业发展计划包括经常与这些导师会面，出席神经退行性疾病研讨会并发表演讲，参加疾病神经生物学课程，参加临床结果设计课程，经常回顾病理学，特别是tau聚焦病理学，获得小鼠认知行为分析的经验，并完成伦理学和研究科学课程。华盛顿大学医学院（Washington University School of Medicine）拥有出色的指导记录，特别是K奖获得者，并拥有多个专注于神经退行性疾病的实验室。这将为老年研究的指导提供一个丰富和支持性的科学环境。米勒博士有足够（800平方英尺）的实验室空间和设备来完成这个研究项目。

DESCRIPTION (provided by applicant): Dr. Timothy Miller, MD, PhD is an excellently trained, physician scientist with a long standing interest in aging and neurodegenerative disorders. He has recently started as an Assistant Professor in Neurology at Washington University and is now seeking support for further mentorship as he focuses on a novel treatment strategy for Alzheimer's disease and Frontotemporal dementia. Building on prior experience using antisense oligonucleotides to down regulate genes in the brain and spinal cord, Dr. Miller is now using a similar strategy to either decrease overall levels of tau or decrease the 4R:3R tau ratio by changing exon splicing. He will test whether these changes in tau affect behavioral and pathological phenotype in amyloid beta depositing mice or the N279K tau mutation mice. His short term goals are to launch an academic career, expand a small translational research group, obtain independent funding (RO1), and to gain experience with understanding and treating Alzheimer's and Frontotemporal dementia mouse models. Dr. Miller's long term goal is to develop a moderate sized, exciting, research group with real impact on the understanding and treatment of neurodegenerative diseases of aging. To accomplish these goals, he has enlisted two outstanding, experienced researchers in aging research as mentors, David Holtzman and Alison Goate. His career development plan includes frequent meetings with these mentors, attendance and presentation at neurodegeneration focused seminars, attending a Neurobiology of Disease Course, attending a Designing clinical outcomes course, frequently reviewing pathology, especially tau-focused pathology, gaining experience with mouse cognitive behavioral analyses, and completing an Ethics and Research science course. Washington University School of Medicine has an outstanding track record of mentorship, in particular with K awardees and has multiple labs focused on neurodegenerative disorders. This will provide a rich and supportive scientific environment for mentorship in aging research. Dr. Miller has ample (800sq feet) laboratory space and equipment to accomplish this research project. PUBLIC HEALTH RELEVANCE: There are no treatments which substantially delay the progression of Alzheimer's disease or Frontotemporal dementia. This application tests whether changing the amount or the particular form of a protein called tau will improve behavior and pathological changes in mouse models of Alzheimer's disease and Frontotemporal dementia. This novel therapeutic strategy, if successful, would be applicable to treating human dementias.