Mechanisms of apoptotic cell clearance in the human stomach

描述(由申请人提供)：上皮将大量的管腔抗原从下面的胃肠道组织和这个位置分离出来；它是遇到许多病原体的第一个部位。胃上皮细胞来自腺体较深区域的干细胞，当它们向管腔迁移时，这些干细胞会分化。到达凹陷顶部后，上皮细胞死亡，要么滑入腔内，要么被固有层内的吞噬细胞吞噬。包括巨噬细胞和树突状细胞在内的抗原提呈细胞(APC)可以通过吞噬或自噬来清除细菌、细胞碎片和死亡细胞。吞噬凋亡细胞通常是抗炎的，因为它刺激转化生长因子-β的释放。缺乏凋亡细胞受体的小鼠发生结肠炎的事实支持了适当的吞噬作用在控制胃肠道炎症中的重要性。然而，在幽门螺杆菌感染过程中，当上皮细胞凋亡增加时，没有人研究正常或炎症胃组织中吞噬的结果。从人胃肠道粘膜分离的巨噬细胞反应迟钝。然而，在慢性炎症过程中，胃肠道APC细胞失去了这种低反应性，从而导致了炎症。正在测试的假设是，凋亡的胃上皮细胞被抗原提呈细胞识别和吞噬，这一过程调节局部炎症反应。具体地说，我将确定人类上皮细胞吞噬的结果是否调节了与幽门螺杆菌感染相关的炎症。这项应用的目的是确定识别和吞噬人类胃中的凋亡细胞的分子基础，并评估这一过程对健康和疾病中免疫调节的影响。这将在以下特定目标中进行研究：目标1：评估有助于凋亡上皮细胞内化的受体。目的2：确定调节上皮细胞身体吞噬的下游反应。目的3：研究吞噬调节胃炎症的分子基础。目的4：确定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经被研究，但对人类消化道内的细胞凋亡和吞噬上皮细胞的机制及其对宿主局部反应的影响知之甚少。我们知识上的这种差距使拟议中的研究成为一个令人兴奋的新前沿，与人类粘膜免疫，特别是胃免疫生物学具有广泛的相关性。 公共卫生相关性：这项应用将研究吞噬细胞内化凋亡的胃上皮细胞的机制，以及吞噬凋亡的上皮细胞如何影响胃炎。这些研究还提供了一个翻译成分，将直接在人类胃中研究这一过程。这一新信息可能在预防或治疗由感染引发的消化系统疾病方面具有更广泛的治疗应用，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.