Cytokine Regulation of Photoreceptor Gene Expression

光感受器基因表达的细胞因子调节

• 批准号: 7986827
• 负责人: John D Ash
• 金额: $ 37万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-02 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986827
• 关键词: 5' -AMP-activated protein kinase; Affinity; Agonist; Anabolism; Binding; Biogenesis; Blindness; Cell Death; Cell Survival; Cessation of life; Ciliary Neurotrophic Factor; Conceptions; Data; Databases; Disease; Event; Eye; Funding; Gene Expression; Gene Mutation; Genes; Genetic; Goals; Grant; Inherited; Knock-out; Knockout Mice; Knowledge; Learning; Life; Light; Mediating; Metformin; Mitochondria; Mitochondrial Proteins; Mus; Mutate; Mutation; Nuclear; Oncogenes; PIM1 gene; Phosphorylation; Phosphotransferases; Photoreceptors; Play; Regulation; Retina; Retinal Degeneration; Retinal Photoreceptors; Role; STAT3 gene; Signal Transduction; Signaling Protein; Stress; System; Testing; Transcription Coactivator; Up-Regulation; base; cancer cell; cytokine; design; human disease; improved; inherited retinal degeneration; killings; leukemia inhibitory factor; leukemia inhibitory factor receptor; neuroprotection; new therapeutic target; oncostatin M; preconditioning; prevent; promoter; public health relevance; receptor; repaired; research study; retinal neuron; transcription factor

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.

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 数据库中的 150 多个基因已被证明当基因突变时会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因素。通常，失明不是先天性的，而是延迟到五岁、六岁或七岁才发生。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可以存活并发挥作用数十年。这种现象表明视网膜具有内源性的自我保护系统。通过了解这种内源性保护系统如何发挥作用，我们也许能够利用它来进一步延迟甚至完全防止失明。该项目旨在进一步了解保护视网膜感光细胞免受细胞死亡的内源机制。该提案的四个目标是： 确定 PIM 激酶是否是诱导光感受器保护所必需的（目标 1）。确定视网膜光感受器的诱导保护是否是通过增加线粒体生物发生或线粒体修复来实现的（目标 2）。确定通过 PGC-1 活性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（目标 3）。测试我们为增强神经保护活性而开发的新细胞因子（目标 4）。 公共健康相关性：遗传性视网膜变性的特点是视网膜神经元（最常见的是光感受器）的丧失。 Retnet 数据库中的 150 多个基因已被证明当基因突变时会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因素。通常，失明不是先天性的，而是延迟到五岁、六岁或七岁才发生。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可以存活并发挥作用数十年。这种现象表明视网膜具有内源性的自我保护系统。通过了解这种内源性保护系统如何发挥作用，我们也许能够利用它来进一步延迟甚至完全防止失明。该提议与人类疾病高度相关。我们提议确定视网膜如何实现自我保护。此外，我们建议测试两个新的治疗靶点，以确定它们预防或延缓失明的能力。