Function and dysfunction of REST in neurodegeneration

REST 在神经退行性变中的功能和功能障碍

基本信息

批准号：
9890017
负责人：
Marty Fernandez
金额：
$ 9.91万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890017
关键词：
Adult Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Antioxidants Apoptotic Area Binding Binding Sites Bioinformatics Brain Cell Death Cell Line Cells Cellular Stress Cerebrum Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Cognition Cognitive Complex Data Dementia Development Development Plans Down Syndrome Down-Regulation Elderly Elements Environment Exposure to Functional disorder Future Gene Expression Gene Silencing Generations Genes Genetic Genetic Transcription Glutamates Goals Grant Hippocampus (Brain)Human Human Genetics Hyperactive behavior Impaired cognition Impairment Individual Knock-out Knockout Mice Laboratories Link Long-Term Potentiation Measures Membrane Potentials Memory Mentors Messenger RNA Modeling Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurological Models Neurons Neurosciences Nuclear Oxidative Stress Participant Pathology Patients Phenotype Phosphorylation Phosphotransferases Positioning Attribute Presenile Alzheimer Dementia Production Proteins Proteomics Reactive Oxygen Species Reporting Repression Research Research Personnel Research Training Role Slice Sodium Channel Stress Synapses Synaptic plasticity Tauopathies Techniques Training Transcription Repressor Writing age effect aged aging brain career development cohort demented differential expression disease-causing mutation experience extracellular familial Alzheimer disease gamma secretase human disease hyperphosphorylated tau induced pluripotent stem cell nervous system disorder neurodegenerative phenotype neuronal survival neuropathology neuroprotection normal aging overexpression patch clamp receptor religious order study response reuptake stem cells stressor tau Proteins tau expression tau-1 tau-protein kinase therapeutic target tool transcription factor REST transcriptome sequencing voltage

项目摘要

Abstract The repressor element 1-silencing transcription factor/neuron-restrictive silencer factor, (REST/NRSF), a transcriptional regulator of neuronal genes during development, has a crucial neuroprotective function in the adult brain. Downregulated in mature neurons, REST is reactivated with normal aging and with cellular stress, regulating a gene network that promotes neuronal survival and reducing the expression of genes related to the amyloid and tau neuropathology of Alzheimer’s disease and Down syndrome. Moreover, REST activity has been shown to be diminished in Alzheimer’s disease and Down syndrome brains. We will evaluate whether genetically encoding high levels of REST activity and responsiveness results in neuroprotection from stress in induced pluripotent stem cell (iPSC)-derived neurons generated from a large group of deeply phenotyped humans from three cohorts: aged individuals with high amyloid and tau pathology and severe dementia at death, age-matched controls, and aged individuals who died with substantial amyloid neuropathology but no cognitive impairment. We also will examine the ability of REST to alleviate neurodegenerative phenotypes in Down syndrome and Alzheimer’s disease human iPSC-derived neurons. Last, we will examine if REST can rescue neurons from the synapse-damaging environment of the aged, demented brain. Our proposed studies will probe intrinsically encoded REST activity and its role in neuroprotection in human neurons encompassing diverse genetic backgrounds and phenotypes. These studies also will interrogate REST’s potential as a therapeutic target in neurodegenerative diseases and will examine the importance of REST function in synaptic plasticity. Completion of this research plan will provide training in key technical areas in which I have no previous research experience: collecting and analyzing -omics-level data, gene editing, and measuring and analyzing synaptic activity. This research and training in new techniques will occur in concert with an ambitious career development plan. This will include coursework in neuroscience and bioinformatics, mentoring, grant writing, and scientific presentations. Mentored training in these scientific areas along with execution of my plans for further career development will be instrumental for my advancement to the position of independent investigator and for achieving my future scientific goals in the field of neuroscience and neurological disease.

抽象的复制元件1分解转录因子/神经元限制性消音因子（REST/NRSF），A 发育过程中神经元基因的转录调节剂在发育过程中具有至关重要的神经保护功能成人大脑。在成熟神经元中下调，静止因正常衰老和细胞应激重新激活，调节促进神经元存活的基因网络并降低与阿尔茨海默氏病和唐氏综合症的淀粉样蛋白和tau神经病理学。此外，休息活动具有我们将评估是否显示出在阿尔茨海默氏病和唐氏综合症大脑中减少的。遗传编码高水平的REST活性和反应能力导致胁迫的神经保护作用诱导多能干细胞（IPSC）衍生的神经元，由大量深层表型产生来自三个队列的人类：具有高淀粉样蛋白和tau病理学的老年人以及严重的痴呆症死亡，年龄匹配的对照和老年人死于大量淀粉样神经病理学，但没有认知障碍。我们还将检查休息能够减轻神经退行性表型的能力唐氏综合症和阿尔茨海默氏病人IPSC衍生的神经元。最后，我们将检查休息是否可以从老化的，痴呆的大脑的突触损害环境中救出神经元。我们提出的研究将探测本质上编码的REST活性及其在人类神经元中神经保护中的作用各种遗传背景和表型。这些研究还将质疑Rest的潜力神经退行性疾病中的治疗靶点，并将检查REST功能在突触中的重要性可塑性。该研究计划的完成将在我没有的关键技术领域提供培训以前的研究经验：收集和分析-omics -level数据，基因编辑以及测量和测量和分析突触活动。这项新技术的研究和培训将与雄心勃勃职业发展计划。这将包括神经科学和生物信息学的课程，心理，授予写作和科学演讲。在这些科学领域进行了指导的培训，并执行我进一步的职业发展计划将有助于我晋升到独立的立场研究人员并实现了我在神经科学和神经系统疾病领域的未来科学目标。