Photoreceptor neuron specific alternative splicing of messenger RNA

 描述（由申请人提供）：我们研究的长期目标是解开失明的遗传原因，并开发治疗这些原因的治疗方法。该提案的目标是剖析光感受器中控制选择性剪接的机制，并确定选择性剪接在塑造光感受器细胞功能中的作用。光感受器细胞表达普遍表达基因的独特亚型。特别地，我们的RNA-seq分析显示在感光细胞中包含较小的外显子“微外显子”。这是普遍的基因是至关重要的纤毛导致我们的主要假设，选择性剪接事件在光感受器的产生和功能的专门阐述纤毛，外段。在这项提案中，我们将产生新的动物模型来研究感光细胞中包含微外显子的机制，并测试这一过程对视觉的重要性。我们提出的研究与NEI的视网膜疾病计划保持一致，以“确定遗传性和视网膜退行性疾病（包括RP）中涉及的基因，确定这些突变的病理生理机制，并确定新的潜在治疗策略，如基因转移，组织和细胞移植，生长因子治疗和药物干预。我们提出的研究对新的治疗方法，如“基因转移”，目前正在过渡到临床竞技场的影响。

 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.