Role of serum amyloid A in interferon-gamma expression and T helper 1 cell differ

描述（申请人提供）：血清淀粉样蛋白A在干扰素-3表达和T辅助1细胞分化中的作用摘要：本研究的目的是确定血清淀粉样蛋白A （SAA）在细胞介导的适应性免疫中的作用。这一目标的实现将扩大目前对适应性免疫的认识，并导致探索自身免疫性疾病的新治疗靶点。我们提出的研究的潜在突破可能是重要的，因为自身免疫性疾病是工业化国家发病率和死亡率的主要原因，影响5-8%的人口。自身免疫在打破免疫系统的自我耐受性后产生，这一过程涉及许多不同的分子，目前对一系列过程知之甚少。自身反应效应CD4+ T细胞与自身免疫性疾病的发病机制有关。许多研究表明，CD4+细胞中产生ifn3的辅助性T (Th) 1亚群和产生il -17的CD4+ (Th17)细胞具有引起炎症和自身免疫性疾病的能力。急性期血浆和炎症组织中SAA的升高长期以来与炎症和自身免疫性疾病（包括类风湿关节炎、动脉粥样硬化和克罗恩病）有关。在过去，我们和其他人报道了SAA具有细胞因子样活性，并刺激IL-8、TNF1、IL-12、IL-6、基质金属蛋白酶和组织因子等促炎因子的分泌，这反过来又确立了SAA作为先天免疫系统中关键的炎症介质的地位。我们最近发表的研究结果也表明SAA诱导单核细胞免疫调节细胞因子IL-23的表达，提示SAA调节T细胞分化的潜在机制。在我们的初步实验中，我们发现SAA刺激T细胞分泌IFN3， IFN3是指导幼稚CD4+ T细胞向Th1细胞分化的关键细胞因子。基于这些令人信服的初步数据，我们建议验证SAA在Th1细胞分化中起重要作用的中心假设，因此SAA可能是自身免疫发病机制的致病因子。我们将在三个具体目标中检验这一假设。目的1：研究saa诱导的IFN3分泌。目的2是确定SAA在Th1细胞分化中的作用。目的3是研究saa刺激的IFN3表达和Th1细胞分化中受体介导的信号机制。这项应用的一个广泛的、长期的目标是了解白细胞活化和炎症性疾病进展的关系。本实验的总体目标是更好地了解急性期蛋白SAA在适应性免疫（特别是细胞介导免疫）中的功能，并确定SAA在炎症性疾病中的作用。除了科学目的之外，这项研究的资金将为我的专业发展提供关键资源，因为它将支持我的研究的继续，从而使我在机构内得到晋升，并有能力吸引未来的主流资金。

DESCRIPTION (provided by applicant): Role of serum amyloid A in interferon-3 expression and T helper 1 cell differentiation Summary: The goal of this study is to determine the role of serum amyloid A (SAA) in the cell mediated adaptive immunity. Achievement of this goal will expand the current understanding of adaptive immunity and lead to exploration new therapeutic targets of autoimmune diseases. The potential breakthrough of our proposed study can be significant because autoimmune diseases are a major cause of morbidity and mortality in the industrialized world, affecting 5-8% of the population. Autoimmunity develops after breaking self-tolerance of the immune system, a process that involves many different molecules and is currently a poorly understood series of processes. Autoreactive effector CD4+ T cells are associated with the pathogenesis of autoimmune disorders. Many studies indicated that the IFN3-producing T helper (Th) 1 subset of CD4+ cells and the IL-17-producing CD4+ (Th17) cells have the capacity to cause inflammation and autoimmune diseases. The elevation of SAA in acute-phase plasma and inflamed tissues has long been associated with inflammatory and autoimmune diseases including rheumatoid arthritis, atherosclerosis, and Crohn's disease. In the past, we and others have reported that SAA possesses cytokine-like activities and stimulates the secretion of pro-inflammatory factors such as IL-8, TNF1, IL-12, IL-6, matrix metalloproteinases and tissue factors, which, in turn, established SAA as a key inflammatory mediator in the innate immune system. Our recently published results also indicated that SAA induces immunoregulatory cytokine IL-23 expression in monocytes, suggesting the potential mechanism for SAA to regulate T cell differentiation. In our preliminary experiments, we showed that SAA stimulates T cells to secrete IFN3, a key cytokine directing the differentiation of naove CD4+ T cells into Th1 cells. Based on these compelling preliminary data, we propose to test the central hypothesis that SAA plays an important role in Th1 cell differentiation and therefore is potentially a causal agent in the pathogenesis of autoimmunity. We will test this hypothesis in three specific aims. Aim 1 is to investigate SAA-induced IFN3 secretion. Aim 2 is to determine the role of SAA in Th1 cell differentiation. Aim 3 is to study the receptor-mediated signaling mechanisms involved in SAA-stimulated IFN3 expression and Th1 cell differentiation. A broad, long-ranging goal of this application is to understand the relationship of leukocyte activation and progression of inflammatory diseases. The overall goal of the experiments in this proposal is to understand better the function of acute-phase protein SAA in adaptive immunity - especially cell-mediated immunity - and establish a role of SAA in inflammatory diseases. In addition to the scientific aims, funding of this research will provide critical resources for my professional development insofar as it will support the continuation of my research and thereby lead to both my promotion within the institution and my ability to attract future mainstream funding. PUBLIC HEALTH RELEVANCE: The experiments proposed in this application will establish a role of SAA in cell-mediated immunity. Moreover, our findings have the potential to provide novel mechanistic insights into signaling events in autoimmune diseases that can lead to the identification of new therapeutic targets for autoimmune diseases.