Beta-Defensins: Mediators of Gastrointestinal Inflammation

描述（由申请人提供）：人体的防御系统可分为两部分，先天免疫系统和适应性免疫系统。先天免疫系统是抵御入侵病原体（如细菌）的第一道防线，存在于植物和所有动物中。反应非常迅速，但通常无法自行清除感染病原体，因此，它会发出信号，要求适应性免疫系统提供帮助。适应性免疫系统在清除体内外来病原体方面具有很强的特异性和专业性，但它的反应较慢，需要时间来发展。最终，入侵的病原体被免疫系统产生的炎症反应清除。然而，长期和过度活跃的炎症反应可能对身体产生有害影响，正如在炎症性肠病（IBD）中所见。先天免疫系统通过被称为toll样受体（TLRs）的受体来识别病原体的成分，从而检测外来病原体，如细菌。tlr位于特化细胞（树突状细胞和巨噬细胞）的表面，与致病成分（激动剂）的结合使它们被激活并释放信使分子（称为细胞因子），进一步刺激先天和适应性免疫系统。先天免疫系统的其他组成部分是排列在胃和肠上的上皮细胞。上皮细胞除了形成抵御病原体入侵的物理屏障外，还分泌一种称为β(2)-防御素的小蛋白质，能够杀死细菌。最近，2-防御素已被证明通过tlr依赖机制激活树突状细胞和巨噬细胞，并可能代表先天和适应性免疫系统之间的联系。以下提案中概述的项目目标是确定2-防御素是否在胃肠道炎症期间的炎症反应中起关键作用。因此，该项目涉及胃肠道炎症产生的免疫方面和机制（即发病机制）。尽管在这些领域进行了大量的研究，但引发和导致炎症反应持续存在的原因尚未完全澄清。从IBD患者获得的证据表明，防御素在活动性疾病期间显著增加。在胃肠道炎症的小鼠模型中也有类似的发现。我们将采用GI炎症实验模型来表征和确定2-防御素在炎症机制介导IBD中的作用。更具体地说，我们将(1)检查它们通过tlr4介导的途径激活树突状细胞和巨噬细胞的能力，并促进随后的促炎性T细胞（适应性免疫）反应；(2)确定缺乏特异性2-防御素（Defb1）的动物是否更容易受到胃肠道炎症的影响。通过评估2-防御素激活免疫细胞的功能，我们将能够进一步确定慢性胃肠道炎症性疾病产生/持续的潜在机制。通过增加我们对这些机制的了解，开发治疗这些疾病的新疗法具有更大的潜力。公共卫生相关性：胃肠道慢性炎症性疾病，如克罗恩病和溃疡性结肠炎，仅在美国就有超过100万人受到影响。近年来，先天免疫系统及其组成部分在慢性胃肠道（GI）炎症中起关键作用的研究越来越明显；然而，他们参与的确切性质仍有待充分阐明。该项目的最终目标是评估β -防御素（先天免疫系统的关键成分）在慢性胃肠道炎症发病机制中的作用。随着我们对胃肠道炎症致病机制的理解和知识的增加，开发新的治疗方法和治疗这些疾病的潜力更大。

DESCRIPTION (provided by applicant): The body's defense system can be divided into two components, the innate and adaptive immune systems. The innate immune system acts as the first line of defense against invading pathogens (e.g., bacteria) and is found in plants and all animals. The response is very rapid, but often is unable to clear the infecting pathogen by itself, and therefore, it signals the adaptive immune system to help. The adaptive immune system is very specific and specialized at eliminating foreign pathogens from the body, but its response is slower and requires time to develop. Eventually, the invading pathogen is removed by the inflammatory response generated by the immune system. However, a prolonged and overactive inflammatory response can have detrimental effects on the body, as is seen in inflammatory bowel disease (IBD). The innate immune system detects foreign pathogens, such as bacteria, by recognizing components of the pathogen via receptors, termed toll-like receptors (TLRs). TLRs are located on the surface of specialized cells (dendritic cells and macrophages) and binding of the pathogenic component (agonist) causes them to become activated and release messenger molecules (called cytokines) that further stimulate the innate and adaptive immune systems. Additional components of the innate immune system are the epithelial cells that line the stomach and intestines. In addition to forming a physical barrier to pathogen invasion, epithelial cells also secrete small proteins, termed beta (2)-defensins, which are capable of killing bacteria. Recently, 2-defensins have been shown to activate dendritic cells and macrophages by a TLR-dependent mechanism and may represent a link between the innate and adaptive immune system. The goal of project outlined in the following proposal is to determine if 2-defensins play a critical role in the inflammatory response seen during gastrointestinal (GI) inflammation. Thus the project deals with the immune aspects and mechanism (i.e., pathogenesis) involved in the generation of GI inflammation. Although a great deal of research has been conducted in these areas, what initiates and causes the inflammatory response to persist has not been fully clarified. Evidence obtained from IBD patients demonstrate that defensins are significantly increased during active disease. Similar findings have been seen in mouse models of GI inflammation. We will employ experimental models of GI inflammation to characterize and determine the role of 2-defensins in the inflammatory mechanism mediating IBD. More specifically, we will (1) examine their ability to activate dendritic cells and macrophages by a TLR4-mediated pathway and promote an ensuing pro- inflammatory T cell (adaptive immune) response and (2) determine if animals lacking a specific 2-defensin, Defb1, are more or less susceptible to gastrointestinal inflammation. By evaluating the function of 2-defensins to activate immune cells, we will be able to further define the potential mechanism involved in the generation/perpetuation of chronic GI inflammatory disorders. By increasing our understanding of these mechanisms, a greater potential exists to develop new therapies to treat these disorders. PUBLIC HEALTH RELEVANCE: Chronic inflammatory diseases of the gastrointestinal tract, such as Crohn's disease and ulcerative colitis affect greater than 1 million people in the United States alone. In recent years, it has become increasingly apparent that the innate immune system and its components play a critical role in chronic gastrointestinal (GI) inflammation; however, the exact nature of their involvement remains to be fully elucidated. The ultimate goal of the proposed project is to evaluate the role of beta-defensins (key components of the innate immune system) in the pathogenesis of chronic gastrointestinal inflammation. By increasing our understanding and knowledge of components involved in the pathogenic mechanism of GI Inflammation, a greater potential exists to develop new therapies and treat these disorders.