Understanding Frontotemporal Dementia Using Drosophila and iPSC Models

使用果蝇和 iPSC 模型了解额颞叶痴呆

基本信息

批准号：
10389678
负责人：
Fen-Biao Gao
金额：
$ 208.65万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10389678
关键词：
3-Dimensional Address Affect Age Aging Alzheimer&apos s Disease American Amyotrophic Lateral Sclerosis Animal Model Anterior Atrophic Brain C9ORF72 Cell model Clinical DNA Sequence Alteration Data Dementia Dipeptides Disease Drosophila genus Drug Targeting Frontotemporal Dementia Frontotemporal Lobar Degenerations Genes Genetic Genetic Screening Immune Response Genes Impaired cognition Induced pluripotent stem cell derived neurons Innate Immune Response Introns Language Modeling Molecular Molecular Target Motor Neuron Disease Muscular Atrophy Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Organoids PGRN gene Paralysed Pathogenicity Pathologic Pathology Pathway interactions Patients Personality Persons Play Population Presenile Dementia Production Proteins RNA Role Social Behavior Suppressor Genes System Techniques Temporal Lobe Testing Therapeutic Intervention Topoisomerase II Toxic effect Translating Up-Regulation X Chromosome Yang base brain tissue disease phenotype effective therapy fly frontotemporal lobar dementia-amyotrophic lateral sclerosis genetic analysis genetic approach global health induced pluripotent stem cell interdisciplinary approach knock-down neurotoxicity novel prefrontal lobe stem cell model therapeutic development transcriptome sequencing

项目摘要

ABSTRACT Dementia in aging populations poses a major global health challenge in years to come. In addition to Alzheimer’s disease (AD), frontotemporal dementia (FTD) is another major form of presenile dementia caused by focal degeneration of the prefrontal and/or temporal lobes. FTD patients show changes in personality, social behaviors, or language production. Currently, effective treatments for FTD still remain elusive and the underlying pathogenic mechanisms are poorly understood. The identification of many genes whose mutations are associated with FTD offers an exciting entry point. Among them a GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 is the most common cause of FTD. This mutation is also the most common genetic cause of amyotrophic lateral sclerosis (ALS), further highlighting the importance of understanding neurotoxicity caused by expanded G4C2 repeats and dipeptide repeat (DPR) proteins translated from both sense and antisense repeat RNAs. In this proposal, we will take advantage of both classical genetics of fruitfly Drosophila and cutting-edge techniques that are applicable to patient neurons differentiated from induced pluripotent stem cells (iPSCs) to identify and characterize potent genetic modifiers of disease phenotypes relevant to C9ORF72-FTD/ALS. These mechanistic studies will help understand molecular pathways involved in these disorders and may also reveal potential effective drug targets for therapeutic interventions.

抽象的除了阿尔茨海默氏症之外，老龄化人口中的痴呆症将在未来几年构成一项重大的全球健康挑战。疾病（AD），额颞叶痴呆（FTD）是另一种主要形式的早老性痴呆，由局灶性 FTD 患者的前额叶和/或颞叶退化表现出人格、社交方面的变化。目前，FTD 的有效治疗方法和潜在的治疗方法仍然难以捉摸。人们对许多突变基因的鉴定知之甚少。与 FTD 相关的提供了一个令人兴奋的切入点，其中第一个是 GGGGCC (G4C2) 重复扩展。 C9ORF72 的内含子是 FTD 最常见的原因，该突变也是 FTD 最常见的遗传原因。肌萎缩侧索硬化症（ALS），进一步强调了了解引起的神经毒性的重要性由有义和反义重复序列翻译而来的扩展 G4C2 重复序列和二肽重复序列 (DPR) 蛋白在这项提案中，我们将利用果蝇的经典遗传学和尖端遗传学。适用于从诱导多能干细胞 (iPSC) 分化而来的患者神经元的技术识别和表征与 C9ORF72-FTD/ALS 相关的疾病表型的有效遗传修饰因子。机制研究将有助于了解这些疾病所涉及的分子途径，也可能揭示治疗干预的潜在有效药物靶点。