Mechanisms and Consequences of Heterochromatin Loss in Tauopathies

描述（由申请人提供）：tau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。阿尔茨海默病影响了大约520万美国人，是美国十大死因中唯一缺乏改善疾病治疗或预防方法的原因。人们越来越认识到，以tau蛋白为基础的疗法可能对治疗AD有效，并有可能用于治疗其他tau蛋白病变的额外好处。不幸的是，我们对tau诱导的神经退行性变的理解的主要差距仍然是治疗干预的障碍。利用概括了这些疾病的许多关键特征的黑眼果蝇tau病的简单遗传模型，以及tau转基因小鼠和人类AD脑组织，我们已经确定了异染色质丢失是tau诱导的神经变性的机制。拟议项目的总体目标是确定异染色质丢失在tau病中的上游介质和下游后果。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，David Pellman博士共同指导，超分辨率显微镜、细胞生物学、生物化学和遗传学方法将用于确定导致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诱导的异染色质损失的后果（Aim II）。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tau病模型中，将导致我们对tau诱导的神经退行性变的理解和疾病修饰疗法的发展取得关键进展。弗罗斯特博士和她的导师之间的正式和非正式的互动。Feany和Pellman将在整个合同期间提供培训和职业指导。在这个奖项的指导阶段，弗罗斯特博士将获得专业技能，这对她作为一名学者的长期成功至关重要，通过布里格姆妇女研究职业办公室和哈佛催化剂提供的课程。建议的研究和职业发展计划对她的科学成长和独立研究者的进步至关重要。

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.