Modulation of RhoA Signaling by the mRNA Binding Protein hnRNPQ1

mRNA 结合蛋白 hnRNPQ1 对 RhoA 信号传导的调节

• 批准号: 8312029
• 负责人: Kathryn Renae Moss
• 金额: $ 3.09万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312029
• 关键词: Actins; Affect; Autistic Disorder; Axon; Binding Proteins; Biological Assay; Biology; Biotin; Brain; Cell Line; Cells; Communication; Couples; Cultured Cells; Cytoplasmic Granules; Dendrites; Dendritic Spines; Development; Disease; Down-Regulation; Excitatory Synapse; Fluorescent in Situ Hybridization; Gene Expression; Genetic Translation; Goals; Growth; Hippocampus (Brain); Immunofluorescence Immunologic; Immunoprecipitation; In Vitro; Intellectual functioning disability; Investigation; Knowledge; Label; Lead; Learning; Link; Luciferases; Maintenance; Mediating; Memory; Messenger RNA; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Morphology; Myoblasts; Natural regeneration; Neurons; Phenotype; Play; Protein Biosynthesis; RNA; Recombinants; Regulation; Reporter; Research; Role; Shapes; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Structure; Synapses; Tertiary Protein Structure; Translations; Untranslated Regions; Vertebral column; autism spectrum disorder; base; crosslink; density; improved; in vivo; inhibitor/antagonist; insight; messenger ribonucleoprotein; molecular phenotype; nerve supply; nervous system disorder; neuron development; neuropsychiatry; novel; novel therapeutics; protein function; research study; response; rhoA GTP-Binding Protein

DESCRIPTION (provided by applicant): Abnormal neuronal morphology is a common theme among intellectual disabilities and autism despite the diverse pathological mechanisms underlying these disorders. Specifically, numerous neuropsychiatric diseases have been demonstrated to present with abnormalities in the morphology of dendritic spines, small actin-rich compartments that protrude from the dendrites. The small GTPase, RhoA, a well-characterized regulator of actin dynamics, has been suggested to play a critical role in regulating the morphology of these actin-rich spines. Our lab has revealed that the mRNA binding protein hnRNPQ1 interacts with RhoA mRNA and downregulation of hnRNPQ1 increases steady state RhoA protein levels without increasing RhoA mRNA levels in cultured cells. Additionally, depletion of hnRNPQ1 causes phenotypes associated with increased RhoA signaling in cultured cell lines and primary neuronal cultures. Furthermore, the reduction in hippocampal neuron dendritic spine density observed upon hnRNPQ1 depletion can be rescued by pharmacological inhibition of the RhoA signaling pathway. These preliminary studies warrant investigation of the possible role of hnRNPQ1 in mediating RhoA protein synthesis and signaling in primary neuronal cultures. The proposed research aims to characterize the interaction between hnRNPQ1 protein and RhoA mRNA (Specific Aim 1) and determine whether hnRNPQ1 regulates RhoA mRNA translation locally in dendrites (Specific Aim 2). Additionally, the role of hnRNPQ1 in regulating dendritic spine morphology and RhoA signaling will be assessed in primary neuronal cultures by depleting hnRNPQ1 and analyzing dendritic spine morphological and molecular phenotypes (Specific Aim 3). We hypothesize that hnRNPQ1 negatively regulates the local translation of RhoA mRNA in dendrites, therefore modulating dendritic spine morphology through altered RhoA signaling. This study attempts to link RhoA expression regulation to RhoA signaling modulation and consequently synaptic development, maintenance and plasticity, which is currently a critical gap in our knowledge. Studying the mechanisms involved in regulating dendritic spine morphogenesis will improve our understanding of intellectual disabilities and autism, which will aid in the development of new treatments for these disorders.

描述（由申请人提供）：尽管这些疾病具有多种病理机制，但神经元形态异常是智力残疾和自闭症的共同主题。具体而言，已经证明许多神经精神疾病在树突状棘的形态中存在异常，从树突上突出的小肌动蛋白隔室。小的GTPase Rhoa是肌动蛋白动力学的特征良好的调节剂，在调节这些富含肌动蛋白的棘的形态中起着至关重要的作用。我们的实验室表明，mRNA结合蛋白HNRNPQ1与RhoA mRNA相互作用，HNRNPQ1的下调会增加稳态RHOA蛋白水平，而无需增加培养细胞中RHOA mRNA水平。另外，HNRNPQ1的耗竭会导致与培养的细胞系和原发性神经元培养物中RHOA信号的增加相关的表型。此外，在HNRNPQ1消耗时观察到的海马神经元树突密度的减少可以通过对RhoA信号通路的药理抑制来挽救。这些初步研究值得研究HNRNPQ1在原代神经元培养物中介导RhoA蛋白合成和信号传导中的可能作用。拟议的研究旨在表征HNRNPQ1蛋白和RhoA mRNA之间的相互作用（特定目标1），并确定HNRNPQ1是否在树突中局部调节RHOA mRNA翻译（特定的目标2）。此外，HNRNPQ1在调节树突状脊柱形态和RhoA信号中的作用将通过耗尽HNRNPQ1并分析树突状脊柱形态和分子表型来评估原发性神经元培养物（特定的目标3）。我们假设HNRNPQ1负调节树突中RhoA mRNA的局部翻译，因此通过改变RhoA信号传导调节树突状脊柱形态。这项研究试图将RhoA表达调节与RhoA信号调节以及因此突触发育，维护和可塑性联系起来，这在我们的知识上是一个关键的差距。研究调节树突状脊柱形态发生的机制将改善我们对智力残疾和自闭症的理解，这将有助于开发这些疾病的新治疗方法。