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

描述（由申请人提供）：本项目将研究一组关键的调节蛋白，细胞因子信号传导抑制因子（SOCS），一个由SOCS 1-7组成的8种细胞内蛋白家族和含丝氨酸诱导的Src同源结构域2蛋白（CIS）在人类阿尔茨海默病（AD）脑和人类神经细胞中的表达。SOCS蛋白通过与细胞因子受体和信号传导蛋白的直接抑制性相互作用来调节STAT途径的信号转导，并靶向这些复合物用于蛋白体降解。SOCS是具有短半衰期的立即早期蛋白质;它们在组织中的存在表明对病理学的持续反应。由于SOCS蛋白参与人类免疫系统疾病的证据正在出现，这提出了基于操纵SOCS活性的治疗策略（例如在AD早期）可能具有临床益处的可能性。中心假设是，某些SOCS基因产物的诱导将是神经保护性的，因为它们对减少炎症的直接和间接后果的作用。我们将在体内检查是否存在与AD病理学相关的每个SOCS的缺陷或过度产生，以及哪些细胞类型表达这些蛋白质。这将在两个特定的目标，采用人脑组织样本，和人脑衍生细胞进行检查。具体目标1：将AD影响的脑中SOCS 1-7 mRNA和蛋白的表达和定位与活化的JAK/STAT、炎症和AD病理学的标志物相关联。这一目标的目的是确定SOCS表达如何与疾病状态相关，以及在细胞水平上它是否与JAK/STAT通路的活化标志物以及炎症和神经变性的其他标志物相关。这一目标不仅将确定哪些SOCS在AD中表达和上调或下调，还将确定它们如何与病理结构相互作用。该目标将研究所有SOCS蛋白的表达，但由于初步结果显示强烈定位于神经元，因此将重点放在SOCS-3上。具体目标二：鉴定并检测诱导小胶质细胞、星形胶质细胞、血管内皮细胞和神经元中SOCS表达的药物，从而降低Ab诱导的炎症活化或神经毒性。该目的的目标是首先确定SOCS表达的细胞类型特异性，其次鉴定在不存在炎性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（广泛用于治疗高胆固醇血症的药物）已显示出这种特性。将使用人小胶质细胞、星形胶质细胞、血管内皮细胞和神经元来探索一系列治疗剂对SOCS表达的影响。其次，我们将确定用这些药物预处理是否降低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.