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

• 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
• 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' 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

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）：蒂莫西米勒博士，医学博士，博士是一位训练有素的医生科学家，长期对衰老和神经退行性疾病感兴趣。他最近开始担任华盛顿大学神经学助理教授，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症的新治疗策略。基于先前使用反义寡核苷酸下调大脑和脊髓中基因的经验，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淀粉样蛋白β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，扩大一个小型的翻译研究小组，获得独立的资金（RO1），并获得理解和治疗阿尔茨海默氏症和额颞叶痴呆小鼠模型的经验。米勒博士的长期目标是发展一个中等规模的，令人兴奋的，研究小组与真实的影响的理解和治疗神经退行性疾病的老化。为了实现这些目标，他聘请了两位杰出的、经验丰富的老龄化研究人员作为导师，大卫霍尔茨曼和艾莉森高特。他的职业发展计划包括经常与这些导师会面，出席和介绍以神经退行性疾病为重点的研讨会，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，特别是以tau为重点的病理学，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。华盛顿大学医学院有着出色的指导记录，特别是与K获奖者，并有多个实验室专注于神经退行性疾病。这将为老龄化研究中的导师制提供丰富和支持性的科学环境。米勒博士有足够的（800平方英尺）实验室空间和设备来完成这个研究项目。 公共卫生相关性：目前还没有任何治疗方法可以显著延缓阿尔茨海默病或额颞叶痴呆症的进展。该应用程序测试了改变称为tau的蛋白质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症小鼠模型的行为和病理变化。这种新的治疗策略，如果成功，将适用于治疗人类痴呆症。