Fusobacterial associated beta defensin inducer

梭杆菌相关β防御素诱导剂

• 批准号: 8187121
• 负责人: AARON WEINBERG
• 金额: $ 47.04万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 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/8187121
• 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

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. PUBLIC HEALTH RELEVANCE: Conventional antibiotics are losing the battle against infectious microbes and secondary infections from medical procedures. Through our research focusing on the body's own antibiotics; i.e., antimicrobial peptides (AMPs), we have identified an agent from a common bacterium found in the human mouth that promotes the release of these AMPs from cells that make up the linings of our body, resulting in protection from harmful bacterial invasion. We propose to study this agent in order to determine if it can be used to bolster the body's own defenses against bad organisms, resulting in fewer infections and improved healing.

描述（由申请人提供）：由粘膜上皮产生的人类B-防御素（HBD）都是抗菌和免疫调节的。我们已经建立了一项新的研究，以利用共生细菌剂，促进粘膜组织中内源性HBD的产生。激发我们工作的总体假设是，将共生细菌分子靶向促进人粘膜中先天反应元件的表达的药物是一种新型的方法，可以满足预防微生物感染的新治疗策略的需求。我们已经分离并表征了一个约14kDa，细胞壁与共生口腔菌杆菌的脂蛋白相关的细胞壁相关，并产生了该药物的重组版本。两者都诱导来自包括口服粘膜在内的许多粘膜身体部位的上皮细胞中的HBD。我们将其称为梭菌相关的β防御蛋白诱导蛋白（FAD-I）。为了有一天能够以一种新颖的方式利用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征以及对人上皮的活性范围有基本的了解。 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产生HBD（AIM III：体内建模和人类口服上皮细胞蛋白质组对FAD-I的反应）。通过我们在核分子细菌学F. f. osteragogical Animants研究中具有专业知识，毒理学研究的经验以及在进行蛋白质组学研究方面的能力，我们非常适合发现FAD-I新型能力的潜力。 公共卫生相关性：常规抗生素正在失去与传染性微生物和医疗程序中的继发感染的斗争。通过我们的研究重点是人体自身的抗生素；即，抗菌肽（AMPS），我们已经从人口中发现的常见细菌中鉴定出一种剂量，从而促进这些AMP从组成我们身体衬里的细胞中释放出来，从而免受有害细菌侵袭的保护。我们建议研究该药物，以确定是否可以用来加强人体自身防御不良生物的防御，从而减少感染和改善的愈合。