Photoreceptor neuron specific alternative splicing of messenger RNA

信使RNA的光感受器神经元特异性选择性剪接

基本信息

批准号：
9188084
负责人：
Visvanathan Ramamurthy
金额：
$ 44.6万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188084
关键词：
Adult Affinity Alternative Splicing Anatomy Animal Model Bardet-Biedl Syndrome Biochemical Biogenesis Blindness CRISPR/Cas technology Cell Transplantation Cells Characteristics Cilia Clinical Defect Detection Development Disease Ectopic Expression Electroretinography Event Exons Foundations Functional disorder Future Gene Transfer Generations Genes Genetic Genetic Transcription Goals Growth Factor Human Impairment Inherited Intervention Knock-out Leber&apos s amaurosis Maintenance Membrane Morphogenesis Morphology Mutation Neurons Nucleotides Outcome Pharmacology Photoreceptors Physiological Precipitation Process Protein Isoforms Proteins Publishing RNA RNA Splicing RNA, Messenger, Splicing RNA-Binding Proteins Regulation Research Retina Retinal Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Reverse Transcriptase Polymerase Chain Reaction Role Shapes Signal Transduction Site-Directed Mutagenesis Structure Testing Therapeutic Tissue Transplantation Tissues Vertebrate Photoreceptors Vision Visual Work base ciliopathy cilium biogenesis experimental study knock-down novel novel therapeutics programs protein complex protein function public health relevance response transcriptome sequencing treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The long term goals of our research are to unravel the genetic causes of blindness and develop therapeutic approaches to treat these causes. The goal of this proposal is to dissect the mechanism controlling alternative splicing in photoreceptors and to determine the role of alternative splicing in shaping the function of photoreceptor cells. Photoreceptor cells express unique isoforms of ubiquitously expressed genes. In particular, our RNA-seq analyses show an inclusion of smaller exons "microexons" in the photoreceptor cells. This is prevalent in genes that are crucial for ciliogenesis leading to ou main hypothesis that alternative splicing events in photoreceptors contribute to the generation and function of specialized elaborated cilium, the outer segment. In this proposal, we will generate novel animal models to study the mechanism behind the inclusion of microexons in photoreceptor cells and test the importance of this process for vision. Our proposed studies are aligned with the Retinal Diseases Program of the NEI to "Identify the genes involved in both inherited and retinal degenerative diseases (including RP), determine the pathophysiological mechanisms underlying these mutations, and determine new potential therapeutic strategies for treatment such as gene transfer, tissue and cell transplantation, growth factor therapy, and pharmacological intervention. Our proposed studies have an implication on novel therapies such as "gene transfer" that are currently transitioning into the clinical arena.

描述（由申请人提供）：我们研究的长期目标是揭示失明的遗传原因并开发治疗这些原因的治疗方法。本提案的目标是剖析控制光感受器中选择性剪接的机制并确定其机制。选择性剪接在塑造感光细胞功能中的作用感光细胞表达普遍表达的基因的独特亚型。特别是，我们的RNA-seq分析显示包含较小的亚型。光感受器细胞中的外显子“微外显子”在对纤毛发生至关重要的基因中普遍存在，导致我们的主要假设是光感受器中的选择性剪接事件有助于专门的纤毛（外部片段）的产生和功能。将生成新的动物模型来研究感光细胞中包含微外显子的机制，并测试该过程对视力的重要性。我们提出的研究与 NEI 的视网膜疾病计划一致，旨在“鉴定与遗传性和视网膜退行性疾病（包括 RP）相关的基因，确定这些突变背后的病理生理机制，并确定新的潜在治疗策略，例如基因转移、组织和细胞移植、生长因子治疗和药物干预我们提出的研究对目前正在进入临床领域的“基因转移”等新疗法具有影响。