PGC-1 coactivators in photoreceptor development and survival

PGC-1 共激活剂在光感受器发育和存活中的作用

基本信息

批准号：
8561075
负责人：
Zoltan P Arany
金额：
$ 57.5万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8561075
关键词：
Acute Adenoviruses Adult Aerobic Alleles Biogenesis Biological Assay Biology Blindness Cell Culture Techniques Cell Respiration Cell Survival Cells Collaborations Data Development Disease Electron Microscopy Electroporation Electroretinography Equilibrium Evaluation Eye Fluorescence Fundus photography Gene Delivery Gene Expression Genetic Genetic Models Genus Hippocampus Harvest Hydrogen Peroxide Injection of therapeutic agent Lead Light Measures Mediating Metabolic Metabolism Mitochondria Modeling Monitor Mus Optics Oxidative Stress Photoreceptors Plasmids Production Reactive Oxygen Species Respiration Retina Retinal Role Saints Source Testing Therapeutic Intervention Tissues Vision Work X-Ray Computed Tomography falls in vivo light microscopy loss of function mouse model novel overexpression oxidative damage photoreceptor degeneration prevent programs public health relevance recombinase response success therapeutic target

项目摘要

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.

概括光感受器（PR）变性是全球失明的主要原因，仍然很了解。公关变性的主要原因被认为是活性氧（ROS）灌输的损害。 PR也是最多的体内高度代谢细胞，这种高氧代谢是一种强的 ROS的来源。 PRS如何发展如此高的有氧能力，以及PRS如何平衡多余的ROS的能力尚不清楚。我们在这里建议测试假设 1）PR线粒体代谢的显着发展增加在产后发育过程中，转录共激活因子PGC-介导 1alpha和beta，其他线粒体代谢的有效调节剂细胞； 2）PGC-1Alpha和Beta同时调节一个反ROS程序，该程序可以篡改以减慢公关变性。我们将用新颖的假设检验这些假设遗传小鼠模型，并采用最新的基因输送方法眼睛。这些研究的成功可能为治疗干预的新途径开放这些毁灭性的疾病。