Fusobacterial associated beta defensin inducer

梭杆菌相关β防御素诱导剂

• 批准号: 8456173
• 负责人: AARON WEINBERG
• 金额: $ 41.93万
• 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/8456173
• 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.

描述（由申请人提供）：人b防御素（hBDs）由粘膜上皮产生，具有抗菌和免疫调节作用。我们已经建立了一条新的研究路线，利用共生细菌促进粘膜组织内源性hBDs的产生。启发我们工作的首要假设是，靶向共生细菌分子作为促进人类粘膜先天反应元件表达的药物是解决预防微生物感染的新治疗策略需求的新方法。我们已经从口腔共生细菌核梭杆菌中分离并鉴定了一种约14kDa的细胞壁相关脂蛋白，并产生了该因子的重组版本；两者都能在包括口腔粘膜在内的许多粘膜体部位的上皮细胞中诱导hBDs。我们将其称为梭杆菌相关β防御素诱导剂（fad - 1）。为了有一天能够以一种新颖的方式利用fad - 1或其衍生物来增强粘膜免疫和抗菌活性，我们需要对fad - 1的分子和体内安全性特征以及在人上皮上的活性范围有一个基本的了解。本研究通过(1)在细菌本身背景下进一步了解fad - 1（目标1:fad - 1诱导表型的分子基础），(2)发现fad - 1促进细胞活化的方法（目标2：涉及受体介导活性的研究），以及(3)在动物模型中确定fad - 1的安全性，并确定fad - 1对产生hBDs的靶细胞的影响(目标3：体内模型和人口腔上皮细胞对fad - 1的蛋白质组反应)。凭借我们在核芽孢杆菌分子细菌学，hBD相关先天免疫方面的专业知识，在毒理学动物研究方面的经验以及开展基于蛋白质组学的研究的能力，我们非常有能力发现fad - 1的新能力的潜力。