Cytokine Regulation of Photoreceptor Gene Expression

描述(申请人提供)：LIF在M�细胞中被诱导表达，以响应由遗传突变引起的光感受器压力。用拮抗剂抑制LIF受体，或敲除光感受器中的辅助受体gp130或信号靶标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度。我们还发现，在光感受器快速退化的过程中，LIF的表达显著减少，我们发表的研究表明，通过保持LIF水平的升高，我们可以显著延缓遗传性退化。这些结果表明，M�ler细胞中LIF的表达对疾病的进展起调控作用。了解LIF在疾病早期的诱导和在疾病后期被抑制的表达，对于了解一种可以确定发病年龄和视网膜退行性变速度的机制是必要的。了解LIF的调控也将有助于识别潜在的靶点，这些靶点可以通过诱导和维持LIF的表达来促进神经元的存活。这个项目的目标是确定诱导LIF表达的机制和与快速变性相一致的表达减少的机制。该提案将确定三个受体信号通路的作用，它们可以协调诱导或维持LIF的表达，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