Mechanisms of apoptotic cell clearance in the human stomach

描述（由申请方提供）：上皮将大量管腔抗原与下面的胃肠道组织和该位置分离;它是遇到许多病原体的第一个部位。胃上皮细胞从腺体深层的干细胞分化而来，随着它们向管腔迁移。到达小窝顶部后，上皮细胞死亡，要么斯劳进入管腔，要么被固有层内的吞噬细胞吞噬。 抗原呈递细胞（APC）包括巨噬细胞和树突状细胞，其可以通过吞噬或自噬作用去除细菌、细胞碎片和死细胞。凋亡细胞的吞噬通常是抗炎的，因为它刺激TGF-β的释放。适当的吞噬作用在控制胃肠炎症中的重要性得到了凋亡细胞受体缺陷的小鼠发展结肠炎的事实的支持。然而，还没有人研究过H. pylori感染时上皮细胞凋亡增加。 从人胃肠道粘膜分离的巨噬细胞是低反应性的。然而，在慢性炎症期间，胃肠APC细胞失去这种低反应性并促进炎症。正在测试的假设是凋亡的胃上皮细胞被抗原呈递细胞识别和吞噬，并且该过程调节局部炎症反应。具体来说，我将确定人类上皮细胞吞噬的结果是否调节与H相关的炎症。幽门感染本申请的目的是确定人胃中凋亡细胞的识别和吞噬的分子基础，并评估该过程对健康和疾病中免疫调节的影响。这将在以下具体目的中进行检查：目的1：评价有助于凋亡上皮细胞内化的受体。目的2：确定调节上皮细胞尸体吞噬的下游反应。目的3：研究吞噬调节胃炎症的分子基础。目的4：研究吞噬分子在人胃中的表达和功能。 虽然先天免疫的许多方面已被研究，很少有人知道的机制，细胞凋亡，上皮细胞吞噬在人体消化道和当地的主机响应的影响。我们知识上的这一差距使得所提出的研究成为一个令人兴奋的新前沿，特别是与人类粘膜免疫和胃免疫生物学具有广泛的相关性。 公共卫生相关性：本申请将研究吞噬细胞内化凋亡胃上皮细胞的机制，以及凋亡上皮细胞的吞噬如何影响胃炎。这些研究还提供了一个翻译组件，将直接在人体胃中研究这一过程。这一新的信息可能具有更广泛的治疗应用，用于预防或治疗由感染引发的消化系统疾病，包括胃炎，炎症性肠病和感染性腹泻。

DESCRIPTION (provided by applicant): The epithelium separates the vast array of luminal antigens from the underlying gastrointestinal tissue and from this position; it serves as the first site to encounter many pathogens. Gastric epithelial cells emerge from stem cells within the deeper regions of the glands that differentiate as they migrate towards the lumen. After reaching the top of the foveolar pits, epithelial cells die and either slough into the lumen or get engulfed by phagocytes within the lamina propria. Antigen presenting cells (APC) including macrophages and dendritic cells can remove bacteria, cellular debris and dead cells through phagocytosis or autophagy. Engulfment of apoptotic cells is generally anti- inflammatory since it stimulates the release of TGF-b. The importance of proper phagocytosis in the control of gastrointestinal inflammation is supported by the fact that mice deficient in a receptor for apoptotic cells develop colitis. However, nobody has ever studied the outcome of engulfment in normal or inflamed gastric tissue during H. pylori infection when epithelial cell apoptosis is increased. Macrophages isolated from human gastrointestinal mucosa are hyporesponsive. However, during chronic inflammation, gastrointestinal APC cells lose this hyporesponsiveness and contribute to the inflammation. The hypothesis being tested is that apoptotic gastric epithelial cells are recognized and engulfed by antigen presenting cells and this process modulates local inflammatory responses. Specifically, I will determine if the outcome human epithelial cell engulfment modulates inflammation associated with H. pylori infection. The objective of this application is to define the molecular basis for the recognition and engulfment of apoptotic cells in the human stomach and to assess the impact of this process on immune regulation in health and disease. This will be examined in the following Specific Aims: Aim 1: Evaluate the receptors contributing to the internalization of apoptotic epithelial cells. Aim 2: Define the downstream responses that regulate the engulfment of epithelial cell corpses. Aim 3: Examine the molecular basis by which engulfment regulates gastric inflammation. Aim 4: Determine the expression and function of engulfment molecules in the human stomach. Although many aspects of innate immunity have been studied, little is known about the mechanisms of apoptotic, epithelial cell engulfment in the human digestive tract and their impact on local host responses. This gap in our knowledge makes the proposed studies an exciting new frontier with broad relevance for mucosal immunity in humans and gastric immunobiology in particular. PUBLIC HEALTH RELEVANCE: This application will examine the mechanisms whereby phagocytes internalize apoptotic gastric epithelial cells and how the engulfment of apoptotic epithelial cells impacts gastritis. These studies also provide a translational component that will investigate this process directly in the human stomach. This new information may have broader therapeutic applications for the prevention or treatment of digestive diseases triggered by infection including gastritis, inflammatory bowel diseases and infectious diarrhea.