Are the suppressors of cytokine signaling involved in Alzheimer's disease?

描述（由申请人提供）：本项目将研究人类阿尔茨海默病（AD）大脑和人类神经细胞中一个关键的调节蛋白组，细胞因子信号抑制蛋白（SOCS），一个由SOCS 1-7和细胞因子诱导的Src同源2结构域蛋白（CIS）组成的8个细胞内蛋白家族的表达。SOCS蛋白通过与细胞因子受体和信号蛋白的直接抑制相互作用来调节STAT通路的信号转导，并靶向这些复合物进行蛋白体降解。SOCS是半衰期短的早期蛋白质；它们在组织中的存在表明对病理的持续反应。随着越来越多的证据表明SOCS蛋白参与人类免疫系统疾病，这提出了一种可能性，即基于SOCS活性的治疗策略，例如早期的AD，可能具有临床益处。核心假设是，某些SOCS基因产物的诱导将具有神经保护作用，因为它们可以减少炎症的直接和间接后果。我们将在体内检查与AD病理相关的每种SOCS是否存在缺陷或过量生产，以及哪些细胞类型表达这些蛋白质。这将在使用人类脑组织样本和人类脑源性细胞的两个特定目标中进行检查。特异性目的1：在AD患者大脑中，SOCS 1-7 mRNA和蛋白的表达和定位与激活的JAK/STAT、炎症和AD病理标志物之间的关系。本研究的目的是确定SOCS表达与疾病状态的相关性，以及在细胞水平上，SOCS表达是否与JAK/STAT通路的激活标记物以及其他炎症和神经变性标记物相关。这一目标不仅将确定哪些SOCS在AD中表达和上调或下调，而且还将确定它们如何与病理结构相互作用。本研究将研究所有SOCS蛋白的表达，但主要关注SOCS-3，因为初步结果显示其强烈定位于神经元。特异性目标2：鉴定和测试诱导SOCS在小胶质细胞、星形胶质细胞、血管内皮细胞和神经元中表达的药物，从而减少Ab诱导的炎症激活或神经毒性。本研究的目的是首先确定SOCS表达的细胞类型特异性，其次确定在缺乏炎症细胞因子的情况下可以诱导SOCS（特别是SOCS-3）表达的治疗剂。辛伐他汀（一种广泛用于治疗高胆固醇血症的药物）具有这种特性。人类小胶质细胞、星形胶质细胞、血管内皮细胞和神经元将被用于探索一系列治疗药物对SOCS表达的影响。其次，我们将确定这些药物预处理是否会降低Ab诱导的炎症指数。

DESCRIPTION (provided by applicant): This project will examine the expression of a key group of regulatory proteins, the suppressor of cytokine signaling (SOCS), a family of 8 intracellular proteins consisting of SOCS 1-7 and cytokine-inducible Src homology 2 domain containing protein (CIS) in human Alzheimer's disease (AD) brains and human neural cells. The SOCS proteins regulate signal transduction of the STAT pathway by direct inhibitory interactions with cytokine receptors and signaling proteins, and to target these complexes for proteosomal degradation. SOCS are immediate early proteins with short half-lives; their presence in tissue indicates ongoing responses to pathology. As evidence is emerging for the involvement of SOCS proteins in diseases of the human immune system, this raises the possibility that therapeutic strategies based on the manipulation of SOCS activity, for example earlier in AD, might be of clinical benefit. The central hypothesis is that induction of certain SOCS gene products will be neuroprotective due to their effects on reducing direct and indirect consequences of inflammation. We will examine in vivo whether there is a deficit or overproduction of each SOCS in relation to AD pathology, and which cell types are expressing these proteins. This will be examined in two specific aims employing human brain tissue samples, and human brain-derived cells. Specific Aim 1: To correlate expression and localization of SOCS 1-7 mRNA and protein in AD affected brains in relation to markers of activated JAK/STAT, inflammation and AD pathology. The goal of this aim is to define how SOCS expression correlates with disease state, and at the cellular level whether it correlates with activated markers of the JAK/STAT pathway and other markers of inflammation and neurodegeneration. This aim will not only determine which of the SOCS are expressed and up-or downregulated in AD, but how they interact with pathological structures. This aim will study expression of all SOCS proteins, but focus on SOCS-3 due to preliminary results showing strong localization to neurons. Specific Aim 2: To identify and test agents that induce expression of SOCS in microglia, astrocytes, vascular endothelial cells and neurons that result in reduced Ab induced inflammatory activation or neurotoxicity. The goal of this aim is to firstly determine the cell type specificity of SOCS expression, secondly identify therapeutic agents that can induce expression of SOCS (particularly SOCS-3) in the absence of inflammatory cytokines. This property has been shown for simvastatin, the agent widely used to treat hypercholesterolemia. Human microglia, astrocytes, vascular endothelial cells and neurons will be used to explore the effects of a range of therapeutic agents on SOCS expression. Secondly, we will determine whether pretreatment with these agents reduce Ab induced inflammatory indices.