Mechanisms Behind Retinal Photoreceptor Cells Outer Segment Biogenesis

项目总结/摘要 我们研究的长期目标是破译控制细胞形态发生的机制。 光感受器外节（OS），一个对我们的视觉至关重要的细胞区室。该提案将具体 研究“进行性视杆细胞视锥细胞变性”（PRCD）在光感受器功能和OS中的作用 生物起源PRCD仅存在于光感受器OS盘膜中，并与 视紫红质拟议的研究也具有临床相关性，因为PRCD突变会导致视网膜炎 色素沉着症（RP）在人类和狗。我们最近的研究表明，PRCD是一种后脂肪性疾病， 在唯一的半胱氨酸（Cys 2）中通过“棕榈酰化”修饰，该半胱氨酸与人和狗中的RP连接 （Cys2Tyr）。尽管PRCD在视网膜功能中的重要性，但PRCD在光感受器中的作用并不重要。 这是已知的，并且是本申请的主要焦点。本研究的第一个目的将探讨PRCD的作用 使用通过CRISP-Cas9基因组编辑产生的新型PRCD-KO动物模型在光感受器中进行。的 第二个目标是确定PRCD中常见的患者突变（C2 Y）如何导致视网膜色素变性 (RP)使用多种转基因动物模型。我们提出的研究与视网膜疾病 NEI计划：“确定遗传性和视网膜退行性疾病相关的基因 （包括RP），确定PRCD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。

PROJECT SUMMARY/ABSTRACT The long-term goal of our study is to decipher the mechanisms controlling the morphogenesis of the photoreceptor outer segment (OS), a cellular compartment vital for our vision. This proposal will specifically investigate the role of “Progressive Rod Cone Degeneration” (PRCD), in photoreceptor function and OS biogenesis. PRCD is exclusively present in photoreceptor OS disc membranes and associates with rhodopsin. The proposed studies are also clinically relevant as mutations in PRCD cause retinitis pigmentosa (RP) in humans and dogs. Our recent study showed that PRCD is post-translationally lipid modified by “palmitoylation” in a sole cysteine (Cys2), which is linked with RP in humans and dogs (Cys2Tyr). Despite the importance of PRCD in retinal function, the role for PRCD in photoreceptors is not known and is the main focus of this application. The first aim of this study will investigate the role of PRCD in photoreceptors using a novel PRCD-KO animal model generated by CRISP-Cas9 genome editing. The second aim will determine how the common patient mutation (C2Y) in PRCD leads to retinitis pigmentosa (RP) using multiple transgenic animal models. 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 PRCD mutations, and determine new potential therapeutic strategies for treatment such as gene transfer, tissue and cell transplantation, growth factor therapy, and pharmacological intervention.