Mechanisms and Consequences of Heterochromatin Loss in Tauopathies

描述(申请人提供)：tau病，包括阿尔茨海默病(AD)和额颞部痴呆，是一种退行性疾病，其特征是在受影响的个人的大脑中聚集的tau蛋白。据估计，AD影响了520万美国人，是美国前十名中唯一缺乏疾病修正疗法或预防方法的死亡原因。越来越多的人认识到，基于tau的疗法在治疗AD方面可能是有效的，另外还有一个好处，即可能被用于治疗其他tau病。不幸的是，我们对tau诱导的神经变性的理解上的主要差距仍然是治疗干预的障碍。利用一个简单的果蝇互变遗传模型，该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，我们已经确定异染色质丢失是tau诱导的神经退化的机制。拟议项目的总体目标是确定异染色质丢失在变态反应性疾病中的上游介体和下游后果。该奖项的K99阶段将在布里格姆妇女医院和哈佛医学院进行，由Mel Feany博士指导和David Pellman博士共同指导，其中将使用超分辨率显微镜、细胞生物学、生化和遗传学方法来确定导致甲状腺疾病异染色质丢失的机制(AIM I)。在该奖项的独立阶段，将使用小RNA测序和其他生化和遗传方法来确定tau诱导的异染色质丢失(AIM II)的后果。将经典和高度创新的技术与新的假设和靶点相结合，在一个描述良好的相互作用模型中，将导致我们对tau诱导的神经变性的理解和疾病修正疗法的发展的关键进展。弗罗斯特博士与她的导师费尼博士和佩尔曼博士之间的正式和非正式互动将在整个奖项期间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里格姆和S研究职业办公室和哈佛大学催化剂提供的课程，获得对她作为一名学者的长期成功至关重要的专业技能。拟议的学习和职业发展计划是她科学成长和晋升为独立调查员的核心。

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.