Cytokine Regulation of Photoreceptor Gene Expression

光感受器基因表达的细胞因子调节

• 批准号: 8630345
• 负责人: John D Ash
• 金额: $ 36.15万
• 依托单位: UNIVERSITY OF FLORIDA
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630345
• 关键词: 3' Untranslated Regions; Age of Onset; Binding; Binding Sites; Cells; Data; Disease; Disease Progression; Elements; Endothelin; Endothelin B Receptor; Endothelin-2; Feedback; Funding; Gene Expression; Goals; Health; In Vitro; Inherited; Knock-out; Knockout Mice; Lead; Ligands; Light; Maintenance; MicroRNAs; Mus; Mutation; Neural Retina; Patients; Phase; Photoreceptors; Play; Publishing; Receptor Signaling; Regulation; Reporter Genes; Retina; Retinal Degeneration; Role; STAT3 gene; Signal Pathway; Signal Transduction; Stress; System; TLR2 gene; Time; Toll-Like Receptor 2; cis acting element; cytokine; leukemia inhibitory factor; leukemia inhibitory factor receptor; mRNA Stability; neuronal survival; neuroprotection; photoreceptor degeneration; prevent; promoter; receptor; response

Abstract: LIF expression is induced in M¿ller cells in response to photoreceptor stress caused by inherited mutations. Inhibiting the LIF receptor with antagonists, or knocking out the co-receptor gp130, or the signaling target STAT3 in photoreceptors, accelerates degeneration. These results show that induced LIF delays the onset and rate of retinal degeneration. We have also shown that expression of LIF decreases significantly during the time of rapid photoreceptor degeneration, and our published studies show that we can dramatically delay inherited degeneration by keeping LIF levels elevated. These results show that progression of disease is regulated by expression of LIF in M¿ller cells. Understanding both the induction of LIF early in disease and its suppressed expression later in disease is necessary to understand one mechanism that can determine the age of onset and rate of retinal degeneration. Understanding the regulation of LIF would also lead to the identification of potential targets that can be manipulated to promote neuronal survival by inducing and maintaining LIF expression. The goal of this project is to determine both the mechanism for induced LIF expression and the mechanism for reduction of expression that coincides with rapid degeneration. The proposal will determine the role of three receptor-signaling pathways that can coordinate to either induce or maintain LIF expression, and will determine the role to the LIF cis-acting elements in suppressing LIF expression

摘要： LIF表达在M？ller细胞中被诱导，以响应由以下引起的光感受器应激： 遗传突变用拮抗剂抑制LIF受体，或敲除辅助受体 gp130或光感受器中的信号传导靶点STAT3加速退化。这些 结果显示诱导的LIF延迟视网膜变性的发生和速率。我们还 表明LIF的表达在光感受器快速感光期间显著降低， 退化，我们发表的研究表明，我们可以显着延迟遗传 通过保持LIF水平升高来进行变性。这些结果表明，疾病的进展是 受M？ller细胞中LIF表达的调节。了解LIF的诱导早期， 疾病及其在疾病后期的抑制表达是必要的，以了解一个 这是一种可以确定视网膜变性发病年龄和发病率的机制。理解 LIF的调节也将导致识别潜在的靶点， 通过诱导和维持LIF表达来促进神经元存活。目标 本项目的目的是确定诱导LIF表达的机制和 与快速变性一致的表达减少的机制。该提案 将确定三种受体信号通路的作用，这些通路可以协调诱导 或维持LIF表达，并将决定LIF顺式作用元件在 抑制LIF表达