Induced Pluripotent Stem Cells and Drosophila Models of C9ORF72-Related FTD/ALS

C9ORF72 相关 FTD/ALS 的诱导多能干细胞和果蝇模型

基本信息

批准号：
9888450
负责人：
Fen-Biao Gao
金额：
$ 46.98万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888450
关键词：
Address Affect Age American Amyotrophic Lateral Sclerosis Animal Model Anterior Atrophic Binding Bioinformatics Biological Models C9ORF72 Cell Line Cell model Cells Clinical Cultured Cells Cytoplasmic Inclusion DNA Damage DNA Sequence Alteration Defect Dementia Dipeptides Disease Drosophila genus Electrophysiology (science)Enhancers Face Frontotemporal Dementia Genes Genetic Human Impaired cognition Investigation Language Light Mitochondria Modeling Molecular Motor Neuron Disease Motor Neurons Mus Muscular Atrophy Myotonic Dystrophy Nerve Degeneration Neurodegenerative Disorders Neurons Oxidative Stress PGRN gene Paralysed Pathogenicity Pathologic Pathway interactions Patients Personality Pharmacology Phenotype Play Process Production Proteins RNA Research Social Behavior Suppressor Genes Temporal Lobe Therapeutic Therapeutic Intervention Toxic effect Translations Yang Yeasts brain tissue disease phenotype fly frontotemporal lobar dementia-amyotrophic lateral sclerosis genetic approach global health induced pluripotent stem cell knock-down mouse model neurotoxicity new therapeutic target novel nucleocytoplasmic transport overexpression programs small molecule stem cell model targeted treatment therapeutic development

项目摘要

Dementia is one of the greatest global health challenges we face in the 21st century. Frontotemporal dementia (FTD) is the second most common form of dementia among people under the age of 60 and its pathogenic mechanisms are poorly understood. FTD and amyotrophic lateral sclerosis (ALS), a predominantly motor neuron disease, share many clinical, pathological, and genetic features. The rapid identification of an array of genes that cause FTD/ALS has opened exciting opportunities to dissect shared pathogenic molecular pathways that may be effective targets for therapeutic intervention. In this appalication, we study the most common genetic cause of FTD/ALS, a GGGGCC repeat expansion in the C9ORF72 gene. This genetic mutation may cause disease through multiple mechanisms, including neurotoxicity induced by dipeptide (DPR) proteins generated through repeat-associated non-AUG (RAN) translation. To study these diverse pathogenic mechanisms, we take advantage of the power of Drosophila genetics including genetic suppressors and enhancers of different FTD/ALS disease genes. Such studies often reveal totally unexpected molecular pathways that shed light on pathogenic mechanisms and suggest novel therapeutic targets. In addition, cortical neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs) and human patient brain tissues will be used as a complementary approach. This integrated approach—combining genetic, cellular, molecular, electrophysiological, and bioinformatics analyses—will enable us to make significant contributions to dementia research in the years to come.

痴呆症是 21 世纪我们面临的最大的全球健康挑战之一。 (FTD) 是 60 岁以下人群中第二常见的痴呆症，其致病原因是 FTD 和肌萎缩性脊髓侧索硬化症（ALS）（主要是运动性疾病）的机制尚不清楚。神经元疾病具有许多共同的临床、病理和遗传特征，可快速识别。导致 FTD/ALS 的基因为剖析共享致病分子提供了令人兴奋的机会在此应用中，我们研究最多的途径可能是治疗干预的有效目标。 FTD/ALS 的常见遗传原因是 C9ORF72 基因中的 GGGGCC 重复扩增。突变可能通过多种机制引起疾病，包括二肽（DPR）诱导的神经毒性通过重复相关的非 AUG (RAN) 翻译产生的蛋白质来研究这些不同的致病性。机制，我们利用果蝇遗传学的力量，包括基因抑制因子和此类研究常常揭示出完全意想不到的分子特征。此外，这些途径揭示了致病机制并提出了新的治疗靶点。由患者特异性诱导多能干细胞 (iPSC) 和人类患者大脑分化而来的神经元组织将被用作一种补充方法——结合遗传、细胞、分子、电生理学和生物信息学分析——将使我们能够做出重大贡献未来几年的痴呆症研究。