Role of GDNF Family Ligands in Photoreceptor Rescue

描述（由申请人提供）：候选人的长期目标是对视网膜退行性疾病中的光受体细胞死亡进行更好的分子理解，并利用这些信息开发针对这些疾病的新治疗方法。在色素性视网膜炎和老年性黄斑变性等致盲性疾病的发展过程中，感光细胞死亡是最后的、不可逆转的一步。对于患有这些疾病的个人来说，治疗选择有限。一种治疗策略寻求为病变视网膜提供神经营养因子，以延长感光细胞的存活时间。GDNF家族配体（GFLs）及其各自的GDNF家族受体（GFRas）通过Ret酪氨酸激酶激活细胞内信号传导。这些因素是多巴胺能、交感和副交感神经元的有效存活因素。GDNF家族的成员已经定位于视网膜，并可能在视网膜发育和维持中发挥重要作用。候选人赞助商的实验室在确定许多GDNF家族成员的生理作用方面发挥了重要作用。实验室拥有所有可用的资源，包括小鼠模型、抗体、探针和现有的专业知识，以促进这项研究计划的成功完成。在赞助人的指导下，候选人拟研究gfl在正常视网膜发育中的功能，并评估其在视网膜变性模型中减缓光感受器细胞死亡的能力。他将(1)确定GDNF家族成员在正常小鼠视网膜中的时空表达模式，(2)确定GFLs、GFRas和Ret中功能丧失突变产生的视网膜表型，以及(3)研究GFLs中功能获得突变是否可以减缓视网膜变性小鼠的光感受器细胞死亡。

DESCRIPTION (provided by applicant): The candidate's long-term aims are to develop a better molecular understanding of photoreceptor cell death in retinal degenerative diseases, and to use this information to develop novel treatments for these conditions. Photoreceptor cell death is the final, irreversible step in the progression of blinding diseases such as retinitis pigmentosa and age-related macular degeneration. Limited treatment options are available for individuals with these conditions. One therapeutic strategy seeks to provide neurotrophic factors to the diseased retina in an effort to prolong photoreceptor cell survival. The GDNF family ligands (GFLs) in conjunction with their respective GDNF family receptors (GFRas) activate intracellular signaling through the Ret tyrosine kinase. These factors are potent survival factors for dopaminergic, sympathetic, and parasympathetic neurons. Members of the GDNF family have been localized to the retina, and may play important roles in retinal development and maintenance. The laboratory of the candidate's sponsor has been instrumental in defining the physiologic roles of many of the GDNF family members. The laboratory has all the available resources, including mouse models, antibodies, probes, and the expertise currently in place to facilitate successful completion of this research proposal. With the guidance of his sponsor, the candidate proposes to investigate the function of the GFLs in normal retinal development and to assess their ability to slow photoreceptor cell death in models of retinal degeneration. He will (1) determine the spatial and temporal expression patterns of GDNF family members in the normal murine retina, (2) determine the retinal phenotype produced by loss-of-function mutations in the GFLs, GFRas, and Ret, and (3) to investigate whether gain-of-function mutations in GFLs can slow photoreceptor cell death in mice with retinal degeneration.