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）：候选人的长期目标是更好地了解视网膜退行性疾病中感光细胞死亡的分子机制，并利用这些信息为这些疾病开发新的治疗方法。光感受器细胞死亡是致盲性疾病（如视网膜色素变性和老年性黄斑变性）发展的最后一步，也是不可逆的一步。有限的治疗方案可用于这些条件的个人。一种治疗策略寻求向患病的视网膜提供神经营养因子以努力延长感光细胞存活。GDNF家族配体（GFL）与其各自的GDNF家族受体（GFRa）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存活因子。GDNF家族成员定位于视网膜，并可能在视网膜发育和维持中发挥重要作用。候选人的赞助商的实验室在确定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的资源，包括小鼠模型，抗体，探针和现有的专业知识，以促进成功完成这项研究提案。在其赞助商的指导下，候选人提议研究GFLs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感光细胞死亡的能力。他将（1）确定GDNF家族成员在正常小鼠视网膜中的空间和时间表达模式，（2）确定由GFLs，GFras和Ret中的功能缺失突变产生的视网膜表型，以及（3）研究GFLs中的功能获得突变是否可以减缓视网膜变性小鼠的感光细胞死亡。