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

描述(申请人提供)：这个项目将研究一组关键的调控蛋白，细胞因子信号转导抑制因子(SOCS)，一个由SOCS 1-7和细胞因子诱导的Src同源2结构域包含蛋白(CIS)组成的8个细胞内蛋白家族在人类阿尔茨海默病(AD)大脑和人类神经细胞中的表达。SOCS蛋白通过直接抑制与细胞因子受体和信号蛋白的相互作用来调节STAT通路的信号转导，并针对这些复合体进行蛋白酶体降解。SOC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蛋白参与了人类免疫系统的疾病，这增加了基于控制SOCS活性的治疗策略的可能性，例如在AD的早期，可能会有临床益处。中心假设是，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病理有关的每种SOC是否存在缺陷或过度生产，以及哪些细胞类型表达这些蛋白。这将通过使用人脑组织样本和人脑衍生细胞的两个特定目标来检验。具体目的1：探讨阿尔茨海默病患者脑组织中SOCS1-7mRNA和蛋白的表达和定位与JAK/STAT活化标志物、炎症反应和AD病理的关系。这一目的的目的是确定SOCS的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途径的激活标记以及其他炎症和神经退变的标记相关。这一目标不仅将决定哪些SOC在AD中表达和上调或下调，而且它们如何与病理结构相互作用。这个目标将研究所有SOCS蛋白的表达，但由于初步结果显示SOCS-3强烈定位于神经元，因此将重点放在SOCS-3上。特定目的2：鉴定和测试诱导小胶质细胞、星形胶质细胞、血管内皮细胞和神经元中SOCs表达的药物，以减少抗体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，然后寻找在没有炎性细胞因子的情况下能够诱导SOCS(特别是SOCS-3)表达的治疗药物。被广泛用于治疗高胆固醇血症的辛伐他汀就表现出了这种特性。将利用人的小胶质细胞、星形胶质细胞、血管内皮细胞和神经元来探索一系列治疗药物对SOCs表达的影响。其次，我们将确定这些药物的预处理是否能降低抗体诱导的炎症指数。

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.