Fusobacterial associated beta defensin inducer

梭杆菌相关β防御素诱导剂

基本信息

批准号：
8286091
负责人：
AARON WEINBERG
金额：
$ 45.13万
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8286091
关键词：
Address Adjuvant Affect Amino Acid Sequence Animal Model Animals Antibiotics Antigen-Presenting Cells Apoptotic Bacteria Bacteriology Biochemical Candidate Disease Gene Cell Wall Cells Characteristics Defense Mechanisms Defensins Dose Epidermal Growth Factor Receptor Epithelial Cells Epithelium Escherichia coli Fusobacterium nucleatum G-Protein-Coupled Receptors Gene Proteins Genome Gram-Negative Bacteria Healed Heating Heterodimerization Human Immune Immune response Immune system Immunocompetent Infection Inflammatory Inflammatory Response Invaded Investigation Lead Ligands Lipoproteins Mediating Mediator of activation protein Medical Metalloproteases Microbe Molecular Mucosal Immunity Mucous Membrane Natural Immunity Oral Oral cavity Oral mucous membrane structure Organism PAWR protein Pathway Analysis Pathway interactions Peptide Sequence Determination Peptides Phagocytes Phenotype Porphyromonas gingivalis Positioning Attribute Procedures Process Production Protein Sequence Alteration Proteins Proteome Proteomics RNA Interference Receptor Activation Recombinants Reporting Research Response Elements Safety Site Skin Toll-Like Receptor 2 Toll-like receptors Vagina Work antimicrobial antimicrobial peptide base beta-Defensins commensal microbes corneal epithelium cytokine experience healing improved in vivo in vivo Model keratinocyte killings mRNA Expression microbial novel novel therapeutics oral bacteria prevent receptor response safety study secondary infection

项目摘要

DESCRIPTION (provided by applicant): Human b-defensins (hBDs), produced by mucosal epithelium, are both antimicrobial and immunoregulatory. We have established a new line of investigation of harnessing commensal bacterial agents that promote production of endogenous hBDs in mucosal tissues. The overarching hypothesis that inspires our work is that targeting commensal bacterial molecules as agents that promote expression of innate response elements in human mucosa is a novel way of addressing the need for new therapeutic strategies to prevent microbial infections. We have isolated and characterized a ~14kDa, cell wall associated lipoprotein from the commensal oral bacterium Fusobacterium nucleatum, and have generated a recombinant version of this agent; both induce hBDs in epithelial cells from numerous mucosal body sites, including the oral mucosa. We refer to this as the Fusobacterial Associated beta Defensin Inducer (FAD-I). To be able, one day, to harness FAD-I or its derivatives in a novel way to bolster mucosal immunity and antimicrobial activity, we require a fundamental understanding of FAD-I's molecular and in vivo safety characteristics and range of activity on human epithelium. This proposal addresses these needs by (1) furthering our understanding of FAD-I in the context of the bacterium itself (Aim I: molecular basis of FAD-I induction phenotypes), (2) discovering the means by which FAD-I promotes cellular activation (Aim II: studies involving receptor mediated activities), and (3) determining the safety of FAD-I in an animal model and identifying the affects FAD-I imparts on the target cells that produce hBDs (Aim III: In vivo modeling and human oral epithelial cell proteome response to FAD-I). With our demonstrated expertise in F. nucleatum molecular bacteriology, hBD related innate immunity, experience in toxicological animal studies and capabilities in conducting proteomics based studies, we are extremely well positioned to discover the potential of FAD-I's novel capabilities.

描述（由申请人提供）：由粘膜上皮产生的人β-防御素（hBD）具有抗菌和免疫调节作用。我们已经建立了利用共生细菌制剂促进粘膜组织内源性 hBD 产生的新研究路线。启发我们工作的首要假设是，将共生细菌分子作为促进人类粘膜先天反应元件表达的试剂，是满足预防微生物感染新治疗策略需求的一种新方法。我们从口腔共生细菌具核梭杆菌中分离并鉴定了约 14kDa 的细胞壁相关脂蛋白，并生成了该试剂的重组版本；两者都会在包括口腔粘膜在内的许多粘膜身体部位的上皮细胞中诱导 hBD。我们将其称为梭杆菌相关 β 防御素诱导剂 (FAD-I)。为了有一天能够以一种新的方式利用 FAD-I 或其衍生物来增强粘膜免疫和抗菌活性，我们需要对 FAD-I 的分子和体内安全特性以及对人类上皮的活性范围有基本的了解。该提案通过以下方式满足这些需求：(1) 进一步加深我们对细菌本身背景下的 FAD-I 的理解（目标 I：FAD-I 诱导表型的分子基础），(2) 发现 FAD-I 促进细胞增殖的方式激活（目标 II：涉及受体介导活性的研究），以及 (3) 在动物模型中确定 FAD-I 的安全性并确定 FAD-I 对产生 hBD 的靶细胞的影响（目标 III：在体内建模和人口腔上皮细胞蛋白质组对 FAD-I 的反应）。凭借我们在具核梭菌分子细菌学、hBD 相关先天免疫方面的专业知识、毒理学动物研究的经验以及进行基于蛋白质组学的研究的能力，我们非常有能力发现 FAD-I 的新功能的潜力。