Cytokine Regulation of Photoreceptor Gene Expression

描述（由申请人提供）：LIF的表达是由遗传突变引起的光感受器应激在M细胞中诱导的。用拮抗剂抑制LIF受体，或敲除共受体gp130，或光感受器中的信号靶点STAT3，都会加速退化。这些结果表明，诱导的LIF延缓了视网膜变性的发生和速率。我们还发现，在光感受器快速变性期间，LIF的表达显著降低，我们发表的研究表明，我们可以通过保持LIF水平升高来显著延缓遗传性变性。这些结果表明，疾病的进展受M细胞中LIF的表达调控。了解LIF在疾病早期的诱导作用及其在疾病后期的抑制表达对于理解一种决定视网膜变性发病年龄和发病率的机制是必要的。了解LIF的调控也将导致识别潜在的靶标，这些靶标可以通过诱导和维持LIF的表达来促进神经元的存活。该项目的目标是确定诱导LIF表达的机制以及与快速变性相一致的表达减少的机制。该提案将确定可以协调诱导或维持LIF表达的三种受体信号通路的作用，并将确定LIF顺式作用元件在抑制LIF表达中的作用

DESCRIPTION (provided by applicant): 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