Mechanisms and Consequences of Heterochromatin Loss in Tauopathies

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，是以聚集的Tau蛋白在受影响个体的脑中积累为特征的退行性病症。据估计，AD影响了520万美国人，并且是美国十大死亡原因中唯一缺乏疾病修饰疗法或预防方法的原因。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蛋白病的额外益处。不幸的是，我们对tau蛋白诱导的神经退行性变的理解存在重大差距，这仍然是治疗干预的障碍。使用一个简单的遗传模型的tau蛋白病在果蝇，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，我们已经确定了异染色质损失的tau蛋白诱导的神经变性的机制。该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Brigham and Women's Hospital和哈佛医学院进行，由Mel Feany博士和大卫佩尔曼博士共同指导，其中超分辨率显微镜，细胞生物学，生物化学和遗传学方法将用于确定导致tau蛋白病异染色质丢失的机制（Aim I）。在该奖项的独立阶段，小RNA测序和其他生物化学和遗传学方法将用于确定tau诱导的异染色质丢失（Aim II）的后果。经典的和高度创新的技术与新的假设和目标相结合，在一个良好的描述模型的tau蛋白病将导致关键进展，我们的理解tau蛋白诱导的神经变性和疾病修饰疗法的发展。Frost博士和她的导师Feany博士和Pellman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，弗罗斯特博士将获得专业技能，这是至关重要的，她作为一个学术通过布里格姆和妇女研究职业办公室和哈佛催化剂提供的课程的长期成功。拟议的研究和职业发展计划是她科学成长和晋升为独立研究者的核心。

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.