Investigating Pathogenic Mechanisms of Frontotemporal Dementia Caused by Mutations in CHMP2B and TBK1

CHMP2B和TBK1突变导致额颞叶痴呆的发病机制研究

基本信息

批准号：
10536397
负责人：
Fen-Biao Gao
金额：
$ 65.41万
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：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536397
关键词：
Address Affect Age American Amyotrophic Lateral Sclerosis Anterior Atrophic Autophagocytosis C9ORF72 Cell Line Chromosome 3 Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA Sequence Alteration Defect Degradation Pathway Dementia Dementia With Amyotrophic Lateral Sclerosis Diagnosis Disease Drosophila genus Endosomes Engineering Exhibits Family Frontotemporal Dementia Genes Genetic Human Impaired cognition Induced pluripotent stem cell derived neurons Investigation Language Link Modeling Molecular Motor Neuron Disease Mus Muscular Atrophy Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nonmuscle Myosin Type IIB Paralysed Pathogenicity Pathologic Pathway interactions Patients Personality Persons Process Production Proteins Recycling Research Series Social Behavior System TBK1 gene Temporal Lobe Testing Therapeutic Intervention Toxic effect Work behavioral phenotyping clinical phenotype experimental study frontotemporal lobar dementia-amyotrophic lateral sclerosis gene discovery induced pluripotent stem cell insight interdisciplinary approach mouse model mutant neural circuit neurodegenerative phenotype new therapeutic target novel prefrontal lobe programs stem cell model syntaxin 13 therapeutic development therapeutic target

项目摘要

ABSTRACT Frontotemporal dementia (FTD) is a progressive neurodegenerative disease associated with focal atrophy of the prefrontal and/or temporal lobes. FTD is the second most common form of dementia among people under the age of 65. Many FTD-causing genes have been identified during the last decade, including CHMP2B, GRN, C9ORF72, and TBK1. Some of these genes are also implicated in the motor neuron disease amyotrophic lateral sclerosis (ALS), paving the way for in-depth mechanistic investigation of pathogenic processes in both disorders. In order to reveal common pathogenic mechanisms in different forms of FTD, it is critically important to investigate both common and rare genetic mutations. To this end, in this application, we will focus on the effects of FTD-causing mutations in CHMP2B and TBK1 on the functions of the endosomal- lysosomal and autophagy pathways, two closely linked cellular pathways for degradation of transmembrane and intracellular cargos. We will take advantage of strengths of different experimental systems including fruitfly Drosophila, mouse models of FTD and cortical neurons differentiated from CRISPR-engineered induced pluripotent stem cells (iPSCs). This multidisciplinary approach will greatly enhance our understanding of pathogenic mechanisms of FTD and reveal novel targets for therapeutic intervention.

抽象的额颞叶痴呆 (FTD) 是一种与局灶性萎缩相关的进行性神经退行性疾病前额叶和/或颞叶。 FTD 是以下人群中第二常见的痴呆症形式 65 岁。在过去十年中，许多 FTD 致病基因已被发现，包括 CHMP2B、 GRN、C9ORF72 和 TBK1。其中一些基因也与运动神经元疾病有关肌萎缩侧索硬化症（ALS），为深入致病机制研究铺平道路两种疾病的过程。为了揭示不同形式 FTD 的共同致病机制，研究常见和罕见的基因突变至关重要。为此，在本申请中，我们将重点关注 CHMP2B 和 TBK1 中引起 FTD 的突变对内体功能的影响溶酶体和自噬途径，两种紧密相连的跨膜降解细胞途径和细胞内货物。我们将利用包括果蝇在内的不同实验系统的优势果蝇、FTD 小鼠模型和 CRISPR 工程诱导分化的皮层神经元多能干细胞（iPSC）。这种多学科方法将极大地增强我们对 FTD 的致病机制并揭示治疗干预的新靶点。