权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Interactions between TDP-43 and microRNA-92 in Drosophila and human neurons

果蝇和人类神经元中 TDP-43 和 microRNA-92 之间的相互作用

基本信息

批准号：
8785309
负责人：
Fen-Biao Gao
金额：
$ 20.94万
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：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8785309
关键词：
3&apos Untranslated Regions Affect Animal Model Behavioral Binding Cell Nucleus Cell physiology Clinical Complex Cytoplasm Defect Dementia Dendrites Dendritic Spines Disease Drosophila genus Ensure Family Foundations Frontotemporal Dementia Gene Expression Gene Mutation Gene Targeting Genes Genetic Genetic Translation Glycoproteins Human Impaired cognition Impairment Laboratories Language Maintenance Mediating Messenger RNA MicroRNAs Modeling Molecular Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuromuscular Junction Neurons Nuclear Other Genetics Pathway interactions Patients Personality Phenotype Process Progranulin Proteins RNA-Binding Proteins Reagent Reproducibility Research Role Social Behavior Societies Structure Synapses Techniques Untranslated RNA Ursidae Family Yang age related aging brain disease phenotype effective therapy fly genetic analysis human DICER1 protein induced pluripotent stem cell insight loss of function member mouse model mutant novel protein TDP-43 public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is a major presenile age-dependent dementia characterized by several clinical features including progressive behavioral changes and language impairments. TDP-43 is a major pathological protein in FTD whose translocation from the nucleus to the cytoplasm in diseased neurons suggests loss of TDP-43 nuclear function may be a key pathogenic mechanism. Several studies including our own implicate defects in the microRNA (miRNA) pathway are one of the important molecular alterations downstream of TDP-43. Using Drosophila as a model, we found that microRNA-92a/b are significantly downregulated in Drosophila TDP-43 (dTDP-43) loss of function mutants. To further understand miRNA functions at the mechanistic level, we generated microRNA-92a, and microRNA-92b single and double mutant fly lines. In this R21 application, we propose molecular, cellular, genetic analyses to further investigate how this nervous system-enriched and evolutionarily conserved but understudied miRNA family functions downstream of TDP-43 to regulate synaptic and dendritic structures in Drosophila and human neurons. These studies will likely provide novel insights into the complex molecular regulatory mechanisms that may contribute to early disease phenotypes in FTD and related neurodegenerative disorders.

描述(申请人提供)：额颞性痴呆(FTD)是一种主要的老年前年龄依赖性痴呆，其临床特征包括进行性行为改变和语言障碍。TDP-43是FTD的主要病理蛋白，其在病变神经元中从胞核移位到胞浆，提示TDP-43核功能丧失可能是其重要的发病机制。包括我们自己在microRNA(MiRNA)途径中的隐含缺陷在内的几项研究是TDP-43下游的重要分子变化之一。以果蝇为模型，我们发现在果蝇TDP-43(dTDP-43)功能缺失突变体中，microRNA-92a/b的表达显著下调。为了在机制水平上进一步了解miRNA的功能，我们构建了microRNA-92a和microRNA-92b单突变和双突变蝇系。在R21的应用中，我们提出了分子、细胞和遗传分析，以进一步研究这个神经系统丰富、进化上保守但未被充分研究的miRNA家族如何在TDP-43下游调节果蝇和人类神经元的突触和树突结构。这些研究可能会为复杂的分子调控机制提供新的见解，这些机制可能有助于FTD和相关神经退行性疾病的早期疾病表型。