Role of GDNF Family Ligands in Photoreceptor Rescue

GDNF 家族配体在光感受器救援中的作用

• 批准号: 6858852
• 负责人: Milam A Brantley
• 金额: $ 15.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858852
• 关键词: cell death; gene expression; gene mutation; genetically modified animals; growth factor receptors; laboratory mouse; ligands; neurogenesis; neurotrophic factors; pathologic process; retina degeneration; visual photoreceptor

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.

描述（由申请人提供）：候选人的长期目标是更好地从分子角度理解视网膜退行性疾病中的感光细胞死亡，并利用这些信息开发针对这些疾病的新疗法。感光细胞死亡是色素性视网膜炎和年龄相关性黄斑变性等致盲疾病进展过程中不可逆转的最后一步。对于患有这些疾病的个人来说，可选择的治疗方案有限。一种治疗策略旨在为患病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 (GFL) 与其各自的 GDNF 家族受体 (GFRas) 结合，通过 Ret 酪氨酸激酶激活细胞内信号传导。这些因子是多巴胺能神经元、交感神经元和副交感神经元的有效生存因子。 GDNF 家族成员定位于视网膜，可能在视网膜发育和维护中发挥重要作用。候选人申办者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。该实验室拥有所有可用资源，包括小鼠模型、抗体、探针以及目前到位的专业知识，以促进该研究计划的成功完成。在资助者的指导下，候选人提议研究 GFL 在正常视网膜发育中的功能，并评估它们在视网膜变性模型中减缓感光细胞死亡的能力。他将 (1) 确定正常鼠视网膜中 GDNF 家族成员的空间和时间表达模式，(2) 确定 GFL、GFRas 和 Ret 功能丧失突变产生的视网膜表型，以及 (3)研究 GFL 的功能获得性突变是否可以减缓视网膜变性小鼠的感光细胞死亡。