PGC-1 coactivators in photoreceptor development and survival

描述（由申请人提供）：光感受器（PR）变性是全球失明的主要原因，但人们对此知之甚少。PR退化的主要原因被认为是活性氧（ROS）造成的损伤。PR也是体内代谢最高的细胞之一，这种高有氧代谢是ROS的强大来源。PR如何发展如此高的有氧能力，以及PR如何平衡这种能力与过量的ROS，尚不清楚。我们在这里提出测试的假设，1）在出生后的发展过程中看到的PR线粒体代谢的显着增长是由转录共激活因子PGC-1 α和β介导的，在其他细胞中线粒体代谢的已知有效调节剂;和2）PGC-1 α和β同时调节抗ROS程序，可以被篡夺，以减缓PR退化。我们将测试这些假设与新的遗传小鼠模型，并与国家的最先进的方法基因输送到眼睛。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.