PGC-1 coactivators in photoreceptor development and survival

描述（由申请人提供）：光感受器（PR）变性是世界范围内失明的主要原因，目前仍知之甚少。PR变性的主要原因被认为是活性氧（ROS）的损伤。pr也是体内代谢水平最高的细胞之一，这种高有氧代谢是ROS的重要来源。PRs是如何发展出如此高的有氧能力的，以及PRs是如何用过量的ROS平衡这种能力的，目前尚不清楚。我们在此提出验证以下假设：1)在出生后发育过程中，PR线粒体代谢的急剧增加是由转录共激活因子PGC- 1α和β介导的，它们是其他细胞中线粒体代谢的有效调节因子；2) pgc -1 α和β同时调节抗ros程序，该程序可以被篡夺以减缓PR变性。我们将用新的遗传小鼠模型和最先进的基因传递方法来测试这些假设。这些研究的成功可能为这些毁灭性疾病的治疗干预开辟新的途径。

DESCRIPTION (provided by applicant): Photoreceptor (PR) degeneration is a leading cause of blindness worldwide, and remains poorly understood. A leading cause of PR degeneration is thought to be damage instilled by reactive oxygen species (ROS). PRs are also some of the most highly metabolic cells in the body, and this high aerobic metabolism is a strong source of ROS. How PRs develop such high aerobic capacity, and how PRs balance this capacity with excess ROS, is not known. We propose here to test the hypotheses that 1) the dramatic developmental increase in PR mitochondrial metabolism seen during post-natal development is mediated by the transcriptional co-activators PGC- 1alpha and beta, known potent regulators of mitochondrial metabolism in other cells; and 2) PGC-1alpha and beta simultaneously regulate an anti-ROS program that can be usurped to slow PR degeneration. We will test these hypotheses with novel genetic mouse models, and with state-of-the-art approaches for gene delivery to the eye. Success in these studies may open new avenues for therapeutic intervention in these devastating diseases.