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: 7706686
• 负责人: Timothy L Denning
• 金额: $ 19.38万
• 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/7706686
• 关键词: A Mouse; Address; Antigen-Presenting Cells; Attention; Automobile Driving; Bacterial Antigens; Biological Assay; Cell Differentiation process; 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; Research; Role; Sentinel; Stimulus; 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）：