A novel pathway for small molecule delivery to Peyer's patch follicles

将小分子递送至派尔氏集结滤泡的新途径

• 批准号: 9222008
• 负责人: Jonathan Chang
• 金额: $ 3.15万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222008
• 关键词: Ablation; Address; Affect; Antibody Formation; Antigens; B-Lymphocytes; Biochemical; Biological; Cells; Cholera Toxin; Collagen; Complex; Data; Dependence; Development; Disease; Dysentery; Enteral; Environment; Epithelial; Epithelial Cells; Epithelium; Extracellular Space; Goals; Immune; Impairment; Infection; Inflammatory; Intestinal Absorption; Intestinal Diseases; Intestines; Ion Transport; Liquid substance; Lymph; Malabsorption Syndromes; Mediating; Microscopy; Molecular; Molecular Weight; Mucosal Immune Responses; Mus; NHE2; Nature; Organ; Pathogenicity; Pathway interactions; Physiological; Population; Process; Role; Route; Signal Transduction; Stromal Cells; Structure; Structure of aggregated lymphoid follicle of small intestine; Surface; System; Testing; Therapeutic; Time; Tissues; Toxin; Transport Process; Water; absorption; adaptive immune response; base; commensal microbes; experimental study; fluid flow; host-microbe interactions; immune function; improved; insight; interest; intestinal epithelium; lymph nodes; microbial; mouse model; novel; public health relevance; response; small molecule; uptake

 DESCRIPTION (provided by applicant): The intestinal microenvironment must be carefully balanced to maintain a mutualistic relationship between host cells and commensal microbes while remaining non-permissive to undesirable pathogenic species. Enteric infection and intestinal disorders correspond to enhanced adaptive immune responses resulting from a breakdown in the normal avenues of host-microbe interactions. Identifying and understanding the means by which signals and antigen present in the intestinal lumen are accessed by host immune cells, and how these means are altered in a diseased state, has thus been a longstanding interest. Our preliminary data suggest that fibroblastic stromal cells located in small intestinal Peyer's patches form a network of collagen-rich reticular conduits which participate in the selective transport of small soluble molecules that have crossed the surface epithelium. Whether this novel avenue of molecular transport renders soluble signals or antigen more accessible to immune cells remains unclear. The first aim of this proposed study will therefore address the possibility that the reticular conduit network of the intestinal Peyer's patc functions as an important, discriminatory avenue for delivery of small molecular weight molecules to the immune cell population of the PP follicle. To this end, we will carefully ascertain the types of molecules permitted within the conduit network and determine the extent to which immune cells resident in the PP are capable of acquiring the signals or antigen that flow through these structures. Interestingly, our preliminary findings also suggest that transport of molecules through these conduit networks require directional fluid flow provided by net water absorption across the epithelium - a process that is often disrupted under conditions of infectious and inflammatory disease. The controlled avenues by which immune cells encounter lumenal contents of the intestine and sense microbial populations likely determine the nature of host-microbe interactions. The second aim of this study will therefore functionally test the possibility that the dependence of conduit-mediated transport on directional fluid flow may functionally limit this pathway under conditions of malabsorption and infectious diarrheal disease. We hypothesize that careful analysis of the extent to which peyer's patch conduits are utilized for intercellular transport of lumenal contents to immune cells, and the sensitivity of ths system to conditions of altered fluid absorption, will yield important insights to microbial sensin and mucosal immune responses.

 描述（由申请方提供）：必须仔细平衡肠道微环境，以维持宿主细胞和肠道微生物之间的互利关系，同时保持不允许不良病原菌种。肠道感染和肠道疾病对应于宿主-微生物相互作用的正常途径的破坏导致的增强的适应性免疫应答。因此，识别和理解宿主免疫细胞进入肠腔中存在的信号和抗原的方式，以及这些方式在疾病状态下如何改变，一直是一个长期的兴趣。我们的初步数据表明，位于小肠派尔集合淋巴结中的成纤维细胞基质细胞形成富含胶原的网状管道网络，其参与穿过表面上皮的可溶性小分子的选择性运输。这种新的分子转运途径是否使可溶性信号或抗原更容易被免疫细胞获得仍不清楚。因此，这项拟议研究的第一个目的是解决肠道派尔氏斑的网状管道网络作为一个重要的，区别性的途径传递小分子量分子到PP滤泡的免疫细胞群的可能性。为此，我们将仔细确定导管网络中允许的分子类型，并确定PP中的免疫细胞能够获得流经这些结构的信号或抗原的程度。有趣的是，我们的初步研究结果还表明，分子通过这些管道网络的运输需要由上皮细胞的净吸水提供的定向流体流动-这一过程在感染性和炎症性疾病的条件下经常被破坏。免疫细胞接触肠道内容物和感知微生物种群的受控途径可能决定了宿主-微生物相互作用的性质。因此，本研究的第二个目的将在功能上测试在吸收不良和传染性支气管炎的条件下，血管内皮细胞介导的转运对定向流体流动的依赖性可能在功能上限制该途径的可能性。我们假设，仔细分析派耶斑导管用于将管腔内容物细胞间转运至免疫细胞的程度，以及系统对液体吸收改变条件的敏感性，将产生对微生物感觉和粘膜免疫应答的重要见解。