PGC-1 coactivators in photoreceptor development and survival

摘要 光感受器(PR)退化是全世界导致失明的主要原因， 人们对此仍然知之甚少。公关退化的一个主要原因被认为是 由活性氧(ROS)灌输的损害。PR也是最多的 体内细胞的高度新陈代谢，而这种高有氧代谢是一种强烈的 ROS的来源。公共关系如何发展出如此高的有氧能力，以及公共关系是如何平衡的 这个ROS超标的容量是未知的。我们建议在这里检验这些假设 1)PR线粒体代谢的显著发育性增加 在出生后发育过程中是由转录共激活因子PGC- 1α和β，已知的线粒体代谢的有效调节者 以及2)PGC-1α和β同时调节抗ROS程序，该程序 可以被篡夺来减缓公关退化。我们将用小说来检验这些假说 基因小鼠模型，以及最先进的基因传递方法 眼睛。这些研究的成功可能会为治疗干预开辟新的途径 这些毁灭性的疾病。

SUMMARY 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 coactivators 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.