The Role of Jam-A in Regulating Intestinal Antigen Presenting Cell Function and I

Jam-A 在调节肠抗原呈递细胞功能中的作用及 I

• 批准号: 7924041
• 负责人: Timothy L Denning
• 金额: $ 23.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924041
• 关键词: A Mouse; Address; Antigen-Presenting Cells; Attention; Automobile Driving; Bacterial Antigens; Biological Assay; Cell physiology; Cells; Colitis; Deltastab; Dendritic Cells; Development; Disease susceptibility; Elements; Enteral; Enterobacteriaceae; Environment; Epithelial; Epithelial Cells; Equilibrium; Functional disorder; Genetic; Genetic Predisposition to Disease; Goals; Homeostasis; Immune; Immune Tolerance; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestinal Diseases; Intestines; Investigation; Lamina Propria; Liquid substance; Microbe; Modeling; Monitor; Mucosal Immune Responses; Mus; Outcome; Pathogenesis; Permeability; Phenotype; Play; Process; Protozoa; Regulation; Regulatory T-Lymphocyte; Research; Role; Sentinel; Stimulus; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Virus; Work; cell type; commensal microbes; design; immune function; in vivo; insight; junctional adhesion molecule; macrophage; microbial; prevent; response; uptake

DESCRIPTION (provided by applicant): Numerous observations have suggested that inflammatory bowel disease is a multifactorial process encompassing at least three major interacting elements: environmental conditions, altered mucosal immune function, and genetic susceptibility factors. While genetic factors and the environment are incredibly difficult to investigate in a controlled manner, attention and research investigation has focused on understanding mucosal immune responses with the working hypothesis being that intestinal inflammation results from a breakdown in immune tolerance to normal intestinal microbiota. While there is increasing understanding of the factors that contribute to the pathogenesis of intestinal inflammation, there is an urgent need for more thoroughly understanding protective factors that control inflammation in order to design more efficacious treatments. An important challenge remains the ability to maintain the critical balance between enforcing tolerance to normal commensal bacteria, while allowing for appropriate mucosal immune responses to pathogenic microbes. Mucosal resident antigen presenting cells (APCs), particularly dendritic cells (DCs) and macrophages, hold great promise in this regard because they can uptake enteric bacteria, viruses, and protozoa and induce distinct types of immune responses, for example pro-inflammatory (Th1/Th17) versus regulatory (Treg/Tr1/Th3) T cells responses. In essence, mucosal APCs are sentinels situated just beneath the epithelial barrier and are capable of initiating and orchestrating intestinal immune responses. Importantly, mucosal DC and macrophage function is closely integrated with overlying intestinal epithelial cells. This intact intestinal layer creates a critical, semi-permeable barrier that allows passage of luminal fluid and molecules between epithelial cells while tightly regulating the flux of the enteric microbiota. Alterations in the integrity of the intestinal epithelial barrier can have a profound impact on intestinal disease susceptibility. While there are associations between increased intestinal epithelial permeability predating the onset of intestinal inflammation, little is understood about how the epithelial barrier regulates innate and adaptive immune cells in the underlying lamina propria. Thus, a clear understanding of the consequences of increased intestinal epithelial permeability created by JAM-A deficiency on the function of lamina propria DCs and macrophages (Specific Aim 1) and detailed analysis of the outcome of JAM-A deficiency in regulation of immune responses during intestinal inflammation (Specific Aim 2) would represent major advancements toward the understanding and treatment of intestinal inflammation, as well as mucosal tolerance and immunity. The overall goal of this proposal is to gain a stronger fundamental understanding of how increased intestinal epithelial barrier permeability regulates the function of lamina propria antigen presenting cells in homeostasis and inflammation. The central hypothesis driving this research is that a "leaky" intestinal epithelial barrier leads to dysfunction of intestinal lamina propria macrophages and dendritic cells and the development of intestinal inflammation.

描述（由申请人提供）： 许多观察表明，炎症性肠病是一个多因素的过程，包括至少三个主要的相互作用的因素：环境条件，改变粘膜免疫功能，遗传易感性因素。虽然遗传因素和环境非常难以以受控的方式进行调查，但注意力和研究调查集中在理解粘膜免疫反应上，其工作假设是肠道炎症是由于对正常肠道微生物群的免疫耐受性的破坏。虽然对导致肠道炎症发病机制的因素有了越来越多的了解，但迫切需要更彻底地了解控制炎症的保护性因素，以便设计更有效的治疗方法。一个重要的挑战仍然是维持对正常肠道细菌的耐受性与允许对病原微生物的适当粘膜免疫应答之间的关键平衡的能力。粘液驻留抗原呈递细胞（APC），特别是树突状细胞（DC）和巨噬细胞，在这方面具有很大的前景，因为它们可以摄取肠道细菌、病毒和原生动物并诱导不同类型的免疫应答，例如促炎性（Th 1/Th 17）与调节性（Treg/Tr 1/Th 3）T细胞应答。本质上，粘膜APC是位于上皮屏障下方的哨兵，能够启动和协调肠道免疫应答。重要的是，粘膜DC和巨噬细胞功能与上覆的肠上皮细胞紧密整合。这种完整的肠层形成了一个关键的半渗透屏障，允许腔液和上皮细胞之间的分子通过，同时严格调节肠道微生物群的流量。肠上皮屏障完整性的改变可对肠道疾病易感性产生深远影响。虽然在肠道炎症发作之前肠上皮通透性增加之间存在关联，但对上皮屏障如何调节下层固有层中的先天性和适应性免疫细胞知之甚少。因此，清楚地了解由JAM-A缺陷引起的肠上皮通透性增加对固有层DC和巨噬细胞功能的影响，（具体目标1）和详细分析JAM-A缺乏在肠道炎症期间调节免疫应答的结果（具体目标2）将代表对肠道炎症的理解和治疗以及粘膜耐受和免疫的重大进展。该提案的总体目标是对肠上皮屏障渗透性增加如何调节固有层抗原递呈细胞在稳态和炎症中的功能有更深入的基本了解。推动这项研究的中心假设是，“渗漏”的肠上皮屏障导致肠固有层巨噬细胞和树突状细胞功能障碍以及肠道炎症的发展。