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.

性状（由申请人提供）：人b-防御素（hBD）由粘膜上皮产生，具有抗菌和免疫调节作用。我们已经建立了一个新的研究路线，利用肠道细菌剂，促进生产内源性hBD的粘膜组织。启发我们工作的总体假设是，靶向肠道细菌分子作为促进人类粘膜中先天反应元件表达的试剂是解决预防微生物感染的新治疗策略需求的新方法。我们已经从口腔粘膜细菌具核梭杆菌中分离并表征了~ 14 kDa的细胞壁相关脂蛋白，并且已经产生了该试剂的重组版本;两者都在来自许多粘膜体部位（包括口腔粘膜）的上皮细胞中诱导hBD。我们将其称为梭菌相关β防御素诱导物（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微生物活性，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。该建议通过以下方式满足这些需求：（1）在细菌本身的背景下进一步了解FAD-I（目的一：FAD-Ⅰ诱导表型的分子基础），（2）发现FAD-Ⅰ促进细胞活化的途径（目标二：涉及受体介导活性的研究），以及（3）确定FAD-1在动物模型中的安全性并鉴定FAD-1对产生hBD的靶细胞的影响（目的III：体内建模和人口腔上皮细胞蛋白质组对FAD-I的响应）。凭借我们在F.我们拥有核质分子细菌学、hBD相关先天免疫、毒理学动物研究经验和进行基于蛋白质组学研究的能力，因此我们非常有能力发现FAD-I的新功能的潜力。 公共卫生相关性：传统抗生素正在失去对抗传染性微生物和医疗程序继发感染的战斗。通过我们对人体自身抗生素的研究，即，为了研究抗菌肽（AMP），我们已经从人类口腔中发现的一种常见细菌中鉴定出一种试剂，该试剂促进这些AMP从构成我们身体衬里的细胞中释放，从而保护免受有害细菌的入侵。我们建议研究这种药物，以确定它是否可以用来加强身体对有害生物的防御，从而减少感染并改善愈合。