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Paneth Cell Secreted Effectors in Mucosal Innate Immunity

粘膜先天免疫中的潘氏细胞分泌效应器

基本信息

批准号：
9295954
负责人：
Charles L Bevins
金额：
$ 46.16万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9295954
关键词：
Agglutination Alleles Animals Autophagocytosis Bacteria Bacterial Infections Binding Biochemical Biological Assay Biological Process Biological Testing Biology C57BL/6 Mouse Carbohydrates Cell physiology Cell secretion Characteristics Chemicals Chronic Code Colitis Communicable Diseases Complement Activation Complementary DNA Crohn&apos s disease Data Disease Enteral Epithelial Cells Equilibrium Foundations Frequencies Functional disorder General Population Genetic Risk Glycols Goals Homeostasis Host Defense Human Ileitis Immune response Immune system Immunity Immunologics Impairment In Vitro Individual Inflammatory Inflammatory Bowel Diseases Innate Immune System Intestines Invertebrates Investigation Knock-out Knowledge Laboratories Lead Lectin Maintenance Mammals Mediating Mediator of activation protein Microbe Modeling Molecular Mucosal Immunity Mucous Membrane Muramidase Mus Names Natural Immunity Nature Orthologous Gene Paneth Cells Pathogenesis Pathogenicity Pathology Pathway interactions Pattern Peptides Phagocytosis Predisposition Property Protein Isoforms Proteins Publishing Recombinants Reporting Risk Factors Role Secretory Vesicles Small Intestines Specimen Surface Testing Urochordata Variant Work alpha-Defensins antimicrobial ascidian base disorder control endoplasmic reticulum stress enteric pathogen experimental study genetic variant host-microbe interactions in vitro activity in vivo innovation insight microbial microbiota misfolded protein novel therapeutic intervention pathogen rare variant receptor response risk variant secretory protein

项目摘要

The immune system of mucosal tissues must effectively protect the host from pathogen invasion, while facilitating homeostatic interactions with a diverse colonizing microbiota. A clear understanding of the key molecules and mechanisms that achieve this delicate balance remains incomplete, leaving a gap in critical knowledge. Paneth cells of the small intestine secrete large quantities of proteins and peptides into the lumen that mediate both interrelated functions of host defense and maintenance of homeostasis. Compelling published evidence from many laboratories, including ours, suggests that defective Paneth cell function increases susceptibility to chronic inflammatory bowel disease (IBD) and to enteric pathogens. This investigation will focus on a secreted protein that our preliminary data suggests is among the most abundant secretory proteins of human Paneth cells, an understudied intestinal lectin named intelectin. Intelectin orthologs widely span the animal Kingdom, from mammals to the invertebrate sea squirts. Recent published data demonstrate that intelectin has molecular pattern binding activity characteristic of the innate immune system, in that it binds to carbohydrates found on a variety microbes - through interaction with exocyclic 1, 2 diols - but does not bind to host carbohydrates because of steric hindrance. Our preliminary data identify qualitative and quantitative aberrations of the two isoforms of intelectin (ITLN1 and ITLN2) in small intestinal specimens from individuals with ileal Crohn's disease (CD) compared to controls. While statistically significant, the mechanisms that may tie these changes to impaired innate immunity in CD are unknown and will be investigated. Our hypothesis, based on published and preliminary data, is that intelectin is a critical mediator of host-microbe interaction in the intestine. Aim 1 will determine the relative expression levels of ITLN1 and ITLN2 in small intestinal CD and control specimens, and biochemically characterize intelectin isolated from human small intestine. Aim 2 will investigate the in vitro activity of intelectin isoforms in vitro. Aim 3 will establish innate immunological consequences of intelectin expression using newly generated C57BL/6 Itln-/- mice. Our goal is to elucidate a fundamental understanding on the role of intelectin in mucosal protection, and in so doing, fill a void in our understanding of a conserved, highly abundant secretory protein of human Paneth cells. Successful completion of these studies will likely have broad impact on our mechanistic understanding of innate immunity in the small intestine.

粘膜组织的免疫系统必须有效地保护宿主免受病原体的侵袭