Mechanisms and Consequences of Heterochromatin Loss in Tauopathies

Tau蛋白病中异染色质丢失的机制和后果

• 批准号: 9173275
• 负责人: Bess Frost
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173275
• 关键词: Actins; Affect; Alzheimer' s Disease; American; Apoptosis; Autopsy; Award; Binding; Biochemical Genetics; Biochemistry; Biogenesis; Biological; Brain; Cause of Death; Cell Cycle; Cell Nucleus; Cells; Code; Complex; Cytoskeleton; DNA; DNA Damage; DNA Transposable Elements; Data; Degenerative Disorder; Development; Development Plans; Disease; Drosophila genus; Drosophila melanogaster; Frontotemporal Dementia; Functional disorder; Genes; Genetic Models; Genetic Transcription; Goals; Growth; Health; Heterochromatin; Homologous Gene; Hospitals; Human; Individual; Intermediate Filaments; Investigation; Lamins; Lead; Mediating; Mediator of activation protein; Mentors; Mentorship; Methods; Microscopy; Modeling; Mus; Nature; Nerve Degeneration; Neurons; Neurosciences; Nuclear; Nuclear Lamin; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Phase; Prevention; RNA Interference; Relaxation; Research; Research Personnel; Resolution; Role; Small RNA; Structure; Tauopathies; Techniques; Testing; Therapeutic Intervention; Tissues; Toxic effect; Training; Transgenic Mice; Transgenic Organisms; United States; Untranslated RNA; Vocational Guidance; Woman; base; brain tissue; career; career development; catalyst; effective therapy; genetic approach; genetic manipulation; human tissue; in vivo; innovation; medical schools; neurotoxicity; novel; piRNA; protein expression; skills; success; tau Proteins; transcriptome sequencing

DESCRIPTION (provided by applicant): Tauopathies, including Alzheimer's disease (AD) and frontotemporal dementia, are degenerative disorders characterized by accumulation of aggregated tau protein in the brains of affected individuals. AD affects an estimated 5.2 million Americans, and is the only cause of death among the top ten in the US that lacks a disease-modifying therapy or method of prevention. It has become increasingly recognized that tau-based therapies may be effective in treating AD, with the added benefit of potentially being used to treat other tauopathies. Unfortunately, major gaps in our understanding of tau-induced neurodegeneration remain a barrier to therapeutic intervention. Using a simple genetic model of tauopathy in Drosophila melanogaster that recapitulates many key features of these diseases, as well as tau transgenic mice and human AD brain tissue, we have identified heterochromatin loss as a mechanism of tau-induced neurodegeneration. The overall goal of the proposed project is to determine the upstream mediators and downstream consequences of heterochromatin loss in tauopathies. The K99 phase of this award will be conducted at Brigham and Women's Hospital and Harvard Medical School under the mentorship of Dr. Mel Feany and co-mentorship of Dr. David Pellman, where super-resolution microscopy, cell biological, biochemical, and genetic approaches will be used to identify the mechanisms leading to heterochromatin loss in tauopathies (Aim I). In the independent phase of this award, small RNA sequencing and other biochemical and genetic approaches will be used to identify the consequences of tau-induced heterochromatin loss (Aim II). The combination of classical and highly innovative techniques with novel hypotheses and targets in a well described model of tauopathy will lead to key advances in our understanding of tau-induced neurodegeneration and the development of disease-modifying therapies. Formal and informal interactions between Dr. Frost and her mentors, Drs. Feany and Pellman, will provide training and career guidance throughout this award. During the mentored phase of this award, Dr. Frost will gain professional skills that are vital to her long-term success as an academic through courses offered through Brigham and Women�s Office of Research Careers and Harvard Catalyst. The proposed studies and career development plan are central to her scientific growth and advancement to independent investigator.

描述（由申请人提供）：Tau蛋白病，包括阿尔茨海默病（AD）和额颞叶痴呆，是一种退行性疾病，其特征是受影响个体大脑中聚集的tau蛋白积累。 AD 影响了大约 520 万美国人，并且是美国十大死亡原因中唯一缺乏疾病缓解疗法或预防方法的疾病。人们越来越认识到基于 tau 的疗法可能有效治疗 AD，并具有潜在用于治疗其他 tau 病的额外益处。不幸的是，我们对 tau 诱导的神经变性的理解存在重大差距，仍然是治疗干预的障碍。利用黑腹果蝇 tau 病的简单遗传模型（概括了这些疾病的许多关键特征）以及 tau 转基因小鼠和人类 AD 脑组织，我们发现异染色质丢失是 tau 诱导的神经变性的机制。拟议项目的总体目标是确定 tau蛋白病中异染色质丢失的上游介质和下游后果。该奖项的 K99 阶段将在布莱根妇女医院和哈佛医学院进行，由 Mel Feany 博士和 David Pellman 博士共同指导，其中超分辨率显微镜、细胞生物学、生化和遗传学方法将用于确定导致 tau蛋白病中异染色质丢失的机制（目标 I）。在该奖项的独立阶段，小 RNA 测序和其他生化和遗传学方法将用于确定 tau 诱导的异染色质丢失的后果（目标 II）。将经典和高度创新的技术与新的假设和目标相结合，在 tau 蛋白病模型中进行充分描述，将在我们对 tau 蛋白诱导的神经变性的理解和疾病缓解疗法的开发方面取得重大进展。弗罗斯特博士和她的导师博士之间的正式和非正式互动。 Feany 和 Pellman 将在整个颁奖过程中提供培训和职业指导。在该奖项的指导阶段，弗罗斯特博士将通过布莱根妇女研究办公室和哈佛催化剂提供的课程获得对她作为学者的长期成功至关重要的专业技能。拟议的研究和职业发展计划对于她的科学成长和晋升为独立研究者至关重要。