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: 7364163
• 负责人: Milam A Brantley
• 金额: $ 17.38万
• 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/7364163
• 关键词: Address; Age related macular degeneration; Animals; Antibodies; Apoptotic; Biological Assay; Brain-Derived Neurotrophic Factor; Cell Death; Cell Survival; Cells; Ciliary Neurotrophic Factor; Code; Condition; Degenerative Disorder; Development; Disease; Enzymes; Family; Family member; GDNF gene; Genes; Individual; Intervention; Knockout Mice; Laboratories; Lead; Ligands; Localized; Maintenance; Mediating; Modeling; Molecular; Mus; Mutation; Nature; Neurons; Pathway interactions; Pattern; Phenotype; Photoreceptors; Phototransduction; Physiological; Play; Protein Overexpression; Protein Tyrosine Kinase; Rattus; Receptor Protein-Tyrosine Kinases; Reporter; Research Proposals; Resources; Retina; Retinal; Retinal Degeneration; Retinitis Pigmentosa; Role; Signal Transduction; Structural Protein; Structure of retinal pigment epithelium; Testing; Therapeutic; Time; Tissues; gain of function mutation; glial cell-line derived neurotrophic factor; loss of function mutation; member; mouse model; mutant; neurotrophic factor; neurturin; novel; persephin; postnatal; receptor

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）：候选人的长期目的是对视网膜退行性疾病中的感光细胞死亡进行更好的分子理解，并使用此信息来为这些疾病开发新的治疗方法。光感受器细胞死亡是盲目疾病（例如色素性视网膜炎和与年龄相关的黄斑变性）进展的最终不可逆步骤。有限的治疗选择可供这些条件下的个人。一种治疗策略旨在为患病视网膜提供神经营养因素，以延长感光细胞的存活。 GDNF家族配体（GFLS）与其各自的GDNF家族受体（GFRAS）一起通过RET酪氨酸激酶激活细胞内信号传导。这些因素是多巴胺能，交感神经和副交感神经元的有效生存因子。 GDNF家族的成员已定位在视网膜上，并可能在视网膜开发和维护中起重要作用。候选人赞助商的实验室在定义许多GDNF家庭成员的生理角色方面发挥了作用。该实验室拥有所有可用的资源，包括鼠标模型，抗体，探针以及目前为促进该研究建议成功完成的专业知识。在他的赞助商的指导下，候选人提议研究GFL在正常视网膜发育中的功能，并评估其在视网膜变性模型中减慢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）确定通过GFL，GFRAS和RET的功能丧失突变产生的视网膜表型，以及（3）调查GFL中的功能性突变是否可以减慢带有鼠标的鼠标伴随鼠标的接收性细胞死亡。