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Fusobacterial Associated Beta Defensin Inducer

梭杆菌相关β防御素诱导剂

基本信息

批准号：
9326495
负责人：
AARON WEINBERG
金额：
$ 47.51万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9326495
关键词：
Address Alanine Antibiotics Bacteria CCL20 gene Categories Cell Wall Cell surface Cells Characteristics Chronic Complex Cysteine Data Development Diglycerides Disease Epithelial Cells Figs - dietary Fusobacterium nucleatum Future Gene Expression Genes Gram-Negative Bacteria Healed Health Heterodimerization Human Immune response In Situ Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intention Intervention Invaded Knowledge Lactobacillus Lipoproteins MAPK8 gene Manuscripts Medical Microbe Mucous Membrane Mus NF-kappa B Ontology Oral Oral cavity Oral mucous membrane structure Orthologous Gene Outcome Peptides Porphyromonas gingivalis Positioning Attribute Probiotics Procedures Progress Reports Property Protease Inhibitor Proteins Reporting Research Response Elements Site Skin Surface System TLR1 gene TLR2 gene Testing Therapeutic Agents Tissues Toxic effect Transcription Factor AP-1 Ubiquitin Up-Regulation Vagina Wound Healing antimicrobial antimicrobial peptide beta-Defensins cathelicidin chemokine corneal epithelium cytokine defense response gastrointestinal healing improved in vitro testing in vivo keratinocyte microbial mouse model mucosal site multicatalytic endopeptidase complex novel novel therapeutics pre-clinical secondary infection translational study

项目摘要

DESCRIPTION (provided by applicant): Human beta defensins (hBDs) are first-line defenders of the host's mucosa against microbial challenges. We were first to report them in Human Oral Epithelial Cells (HOECs) and demonstrated their antimicrobial and immunoregulatory properties as agents that alter inflammatory responses. We believe that harnessing these and other antimicrobial peptides (AMPs) correctly, i.e., promoting their expression in vulnerable sites, could impact the course of infection and wound repair. We have isolated and characterized a cell wall associated molecule from F. nucleatum ATCC 25586 that is principally responsible for hBD induction and refer to it as FAD-I for F. nucleatum Associated beta Defensin Inducer. We have identified that the molecule's activity resides in the cysteine-diacylglycerol complex at position 16, as alanine substitution abrogates activity, and that hBD2 induction is dependent upon interaction of FAD-I with TLRs 1 and 2 on the HOEC surface. Other AMPs are also induced by FAD-I, including Mip3 (CCL20) and LL37 which are elevated in epithelial cells following FAD-I challenge. Moreover, our preliminary data suggests that FAD-I's induction of hBD-2 happens with little simultaneous induction of pro- inflammatory cytokines. Functionally, HOECs challenged with FAD-I are protected from invasion by Porphyromonas gingivalis, a major etiologic agent in the initiation of periodontal destruction. Therefore, our overarching hypothesis is that commensal bacterial molecules, such as FAD-I, that promote the expression of beneficial innate response elements without inflammation, could be harnessed to protect tissues from microbial challenges and inflammatory damage. In order to develop FAD-I into a novel therapeutic agent, we will address several existing knowledge gaps including in vivo tests of FAD-I in various mouse mucosal tissues to determine its' ability to induce in situ AMP expression as well as develop a novel vehicle for delivery of FAD-I for intervention in disease modulation. Our aims are intended to: (1) Determine key characteristics of FAD-I that result in stimulation of epithelial cell-derived AMPs in the absence of an inflammatory response; (2) Determine FAD-I's ability to induce mouse AMP orthologs and quantify pre-clinical FAD-I potency in vivo using the pre-clinical murine models of wound healing and inflammation; (3) Construct a FAD-I producing Lactobacillus for probiotic in vitro testing. Our overall intention is to prepare ourselves to use FAD-I for future translational studies in modulating dysbiosis and chronic inflammation in defined diseased mouse models, which may pave the way for interventional studies in humans.