Cytokine Regulation of Photoreceptor Gene Expression

摘要： 光感受器应激诱导M？ler细胞LiF表达 遗传性突变。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靶标STAT3，加速了退化。这些 结果表明，诱导LIF可延缓视网膜退行性变的发生和发展。我们还有 结果表明，在快速光感受器阶段，LIF的表达显著降低 退化，我们发表的研究表明，我们可以极大地延迟遗传 通过保持LIF水平升高而退化。这些结果表明，疾病的进展是 受M？ler细胞表达LIF的调控。在早期了解LIF的诱导 疾病及其后来在疾病中被抑制的表达是理解一个人所必需的 可以确定视网膜退行性变的发病年龄和比率的机制。理解 对LIF的监管也将导致确定潜在的目标， 通过诱导和维持LIF表达来促进神经元存活。目标是 本项目的目的是确定诱导LIF表达的机制和 与快速退化相一致的表达减少的机制。这项建议 将确定三个受体信号通路的作用，这三个受体信号通路可以协调到 或维持LIF的表达，并将决定LIF在顺式作用元件中的作用 抑制LIF表达式

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