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

痴呆小鼠模型中 tau 蛋白水平和 tau 蛋白亚型的变化

基本信息

批准号：
8013705
负责人：
TIMOTHY M. MILLER
金额：
$ 18.27万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013705
关键词：
Adult Affect Aging Alternative Splicing Alzheimer&apos s Disease Amino Acid Sequence Amyloid Amyloid beta-Protein Antisense Oligonucleotides Behavior Behavioral Birth Brain Cerebrospinal Fluid Clinical Cognitive Data Dementia Deposition Development Plans Disease Doctor of Philosophy Environment Equipment Exclusion Exons Frontotemporal Dementia Funding Future Genes Goals Human Knockout Mice Laboratories Mentors Mentorship Motor Neurons Mus Mutation Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurology Outcome Pathology Patients Peptide Sequence Determination Phenotype Physicians Protein Isoforms Proteins RNA Splicing Research Research Ethics Research Personnel Research Project Grants Science Scientist Spinal Cord Tau isoform ratio Testing Therapeutic TimeLine Training Transgenic Mice Transgenic Organisms Translational Research Universities Washington base career career development design experience foot improved interest knockout animal mature animal medical schools meetings mouse model novel novel therapeutics professor tau Proteins tau mutation treatment strategy

项目摘要

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.

描述（由申请人提供）：Timothy Miller 博士是一位训练有素的医学科学家，对衰老和神经退行性疾病有着长期的兴趣。他最近开始担任华盛顿大学神经病学助理教授，目前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型治疗策略。基于之前使用反义寡核苷酸下调大脑和脊髓基因的经验，Miller 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 的总体水平或降低 4R:3R tau 比率。他将测试 tau 蛋白的这些变化是否会影响β淀粉样蛋白沉积小鼠或 N279K tau 突变小鼠的行为和病理表型。他的短期目标是开展学术生涯，扩大小型转化研究小组，获得独立资助（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规模适中、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，他聘请了两位在衰老研究领域经验丰富的杰出研究人员 David Holtzman 和 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、出席以神经变性为重点的研讨会并进行演讲、参加疾病神经生物学课程、参加设计临床结果课程、经常回顾病理学，尤其是 tau 病理学、获得小鼠认知行为分析的经验，并完成伦理与研究科学课程。华盛顿大学医学院在指导方面有着出色的记录，尤其是对 K 获奖者的指导，并拥有多个专注于神经退行性疾病的实验室。这将为衰老研究的指导提供丰富且支持性的科学环境。米勒博士拥有充足（800 平方英尺）的实验室空间和设备来完成该研究项目。公共卫生相关性：没有任何治疗方法可以显着延缓阿尔茨海默病或额颞叶痴呆的进展。该应用测试改变 tau 蛋白的数量或特定形式是否会改善阿尔茨海默病和额颞叶痴呆小鼠模型的行为和病理变化。这种新颖的治疗策略如果成功，将适用于治疗人类痴呆症。