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

基本信息

批准号：
9189742
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
项目类别：
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/9189742
关键词：
Actins Affect Alzheimer&apos s Disease American Apoptosis Autopsy Award Binding Biochemical Genetics Biochemistry Biogenesis Biological Brain Brain Diseases 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 Heterochromatin Homologous Gene Hospitals Human Individual Intermediate Filaments Investigation Lamins 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 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 new therapeutic target novel protein expression public health relevance skills success tau Proteins tau aggregation transcriptome sequencing

项目摘要

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.

描述（由适用提供）：包括阿尔茨海默氏病（AD）和额颞痴呆在内的tauopathies是退化性疾病，其特征是受影响个体的大脑中聚集的tau蛋白积累。 AD影响了估计的520万美国人，这是美国前十名中唯一缺乏改良疾病疗法或预防方法的死亡原因。已经越来越认识到，基于TAU的疗法可能有效地治疗AD，并有可能被用于治疗其他TAU诱导的神经变性的额外好处仍然是治疗干预的障碍。我们使用果蝇中的tauopathy的简单遗传模型，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，我们已经确定了杂染色质损失是TAU诱导的神经变性的机制。拟议项目的总体目标是确定呼吸蛋白疾病中异染色质损失的上游介体和下游后果。该奖项的K99阶段将在梅尔·菲尼（Mel Feany）博士的心态以及戴维·佩尔曼（David Pellman）博士的心理下在杨百翰和妇女医院和哈佛医学院进行，在那里，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胆汁瘤造成异型蛋白损失的机制。在该奖项的独立阶段，将使用小的RNA测序和其他生化和遗传方法来识别Tau诱导的异染色质损失的后果（AIM II）。经过经典和高度创新的技术与新颖的假设和目标的结合在良好描述的tauopathy模型中，将导致我们对TAU诱导的神经变性的理解以及疾病改良疗法的发展的关键进展。弗罗斯特博士和她的导师Feany博士和Pellman之间的正式和非正式互动将在整个奖项中提供培训和职业指导。在该奖项的指导阶段，Frost博士将获得专业技能，这对于通过Brigham和妇女研究职业办公室和哈佛大学催化剂提供的课程作为学术课程至关重要。拟议的研究和职业发展计划是她对独立研究者的科学成长和进步的核心。