Cytokine Regulation of Photoreceptor Gene Expression

描述（由申请人提供）：遗传性视网膜变性的特征是视网膜神经元（最常见的是光感受器）的丧失。Retnet数据库中有超过150个基因被证明在基因突变时导致某种形式的视网膜变性，这表明这些疾病有很强的遗传成分。通常，失明不是先天性的，而是延迟到生命的第5、6或7个10岁。这种基因突变在受孕时就存在，但光感受器在有害突变的情况下存活并发挥作用数十年。这一现象表明视网膜有一个内源性的自我保护系统。通过了解这个内源性保护系统是如何起作用的，我们也许能够利用它来进一步延缓甚至完全预防失明。该项目旨在进一步了解视网膜光感受器免受细胞死亡的内源性机制。该提案的四个目标将：确定是否需要PIM激酶来诱导光感受器的保护（目的1）。确定视网膜光感受器的诱导保护是通过增加线粒体生物发生还是线粒体修复来实现的（目的2）。确定通过PGC-1活性的基因突变抑制线粒体生物发生或修复是否会阻止预处理诱导的保护（目的3）。测试我们开发的增强神经保护活性的新细胞因子（目标4）。

DESCRIPTION (provided by applicant): Inherited retinal degenerations are characterized by the loss of retinal neurons (most often photoreceptors). More than 150 genes in the Retnet database have been shown to cause some form of retinal degeneration when the gene is mutated, indicating a strong genetic component to these diseases. Often, blindness isn't congenital but is delayed until the 5th, 6th, or 7th decade of life. The genetic mutation is present at conception and yet photoreceptors survive and function for decades with the deleterious mutation. This phenomenon suggests that the retina has an endogenous system of self protection. By learning how this system of endogenous protection functions, we may be able to exploit it to further delay or even prevent blindness altogether. This project was designed to further our knowledge of the endogenous mechanisms by which retinal photoreceptors are protected from cell death. The four aims of this proposal will: Determine whether PIM kinases are required for induced protection of photoreceptors (aim 1). Determine whether induced protection of retinal photoreceptors is brought about through increased mitochondrial biogenesis or mitochondrial repair (aim 2). Determine whether inhibition of mitochondrial biogenesis or repair through genetic mutation of PGC-1 activity prevents preconditioning induced protection (aim 3). Test new cytokines that we developed for enhanced neuroprotective activity (aim 4). PUBLIC HEALTH RELEVANCE: Inherited retinal degenerations are characterized by the loss of retinal neurons (most often photoreceptors). More than 150 genes in the Retnet database have been shown to cause some form of retinal degeneration when the gene is mutated, indicating a strong genetic component to these diseases. Often, blindness isn't congenital but is delayed until the 5th, 6th, or 7th decade of life. The genetic mutation is present at conception and yet photoreceptors survive and function for decades with the deleterious mutation. This phenomenon suggests that the retina has an endogenous system of self protection. By learning how this system of endogenous protection functions, we may be able to exploit it to further delay or even prevent blindness altogether. This proposal is highly relevant to human disease. We are proposing to identify how the retina accomplishes self protection. In addition we are proposing to test two new therapeutic targets to determine their ability to prevent or delay blindness.