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揭开失明的遗传原因，并开发治疗这些原因的方法。这项建议的目的是剖析光感受器中选择性剪接的控制机制，并确定选择性剪接在塑造感光细胞功能中的作用。光感受器细胞表达无处不在的表达基因的独特亚型。特别是，我们的RNA-SEQ分析表明，光感受器细胞中包含了较小的外显子“微外显子”。这在纤毛发生的关键基因中很普遍，这导致了主要的假设，即光感受器中的选择性剪接事件有助于特殊的精细纤毛的产生和功能，纤毛是外节。在这项建议中，我们将建立新的动物模型来研究光感受器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。我们建议的研究与NEI的视网膜疾病计划保持一致，以“确定与遗传性和视网膜退行性疾病(包括RP)有关的基因，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，如基因转移、组织和细胞移植、生长因子治疗和药物干预。我们建议的研究对目前正在过渡到临床领域的”基因转移“等新疗法具有指导意义。

 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.