Ontogeny Of Oral Epithelial Antimicrobial Peptides

口腔上皮抗菌肽的个体发育

• 批准号: 7415215
• 负责人: AARON WEINBERG
• 金额: $ 32.47万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7415215
• 关键词: Adult; Age; Age-Years; Antimicrobial Cationic Peptides; Appearance; Appendix; Bacteria; Bacterial Adhesins; Beginning of Life; Biochemical; Biological; Biological Assay; Birth; Body Fluids; Cell Wall; Characteristics; Child; Complex; Cross-Sectional Studies; Cytoprotection; Data; Defensins; Development; Drug Design; Elderly; Endoribonucleases; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epithelial; Epithelial Cells; Escherichia coli; Fusobacterium nucleatum; Future; Gene Expression; Gram-Negative Bacteria; Growth; HIV-1; Host Defense; Human; Immune; Immune response; Immune system; Immunologist; Individual; Infant; Infection; Inflammation; Injury; Intestines; Invaded; Investigation; Knock-out; Laboratories; Lead; Leukocyte L1 Antigen Complex; Life; Link; Longitudinal Studies; Membrane Proteins; Molecular; Mothers; Mucous Membrane; Natural Immunity; Nature; Oral; Oral cavity; Oral mucous membrane structure; Organism; Outcome; Pancreatic ribonuclease; Peptides; Pilot Projects; Play; Porphyromonas gingivalis; Post-Translational Protein Processing; Property; Proteins; RNA Interference; Range; Regulation; Research Personnel; Resistance; Response Elements; Ribonucleases; Role; SLPI gene; Saliva; Salivary; Source; Staging; Structure; Structure-Activity Relationship; Surface; Tooth structure; Transcript; Up-Regulation; Viral; Weaning; Work; adrenomedullin; age group; age related; antimicrobial; antimicrobial peptide; base; beta-Defensins; beta-defensin-2; commensal microbes; day; design; genome database; infancy; interest; mRNA Expression; microbial; mucosal site; mutualism; novel; novel strategies; oral cavity epithelium; oral commensal; oral tissue; programs; psoriasin; response

DESCRIPTION (provided by applicant): The innate immune system, an evolutionarily ancient response, is believed to be present and functional at birth or within the first few days of life. However, the role commensal bacteria play in "turning on" innate immunity; i.e., regulating it's response, and at what ontogenic point in life this begins to occur is not known. Recent findings in our laboratory are leading us to conjecture that ontogeny of the oral innate immune response may be linked to colonizing organisms in the oral cavity. We recently discovered that Fusobacterium nucleatum, a ubiquitous Gram-negative bacterium of the human oral cavity, induces expression of epithelial cell derived human beta defensin -2 (hBD-2) and hBD-3 in normal oral epithelial cells (NHOECs), resulting in protection against invasion of Porphyromonas gingivalis, a major etiologic agent in periodontal destruction. Extensive biochemical and molecular biological work has identified an F. nucleatum outer membrane protein that induces these antimicrobial and immunoregulatory peptides. We refer to this protein as FAD-I for Fusobacterial associated defensin inducer. Additionally, preliminary cross-sectional data indicates that salivary hBD levels are significantly lower in infancy than in older age groups. We suspect that an age-related association with hBD induction, and possibly other epithelial cell derived antimicrobial peptides (AMPs), is correlated with colonization and persistence of FAD-I expressing F. nucleatum strains. Clearly we need to know more about this dynamic by (1) conducting epidemiologic studies to investigate AMP levels across the age spectrum to establish overall, age stratified and FAD-I associated distributions; (2) determining the inductive properties of FAD-I on AMPs and their subsequent contribution to NHOEC protection and (3) further characterizing the functionality of FAD-I by taking molecular and biochemical approaches to ascertain preliminary structure-function relationships in hBD induction. By better understanding the ontogenic spectrum of an individual's innate immune AMP profile, we may be able to identify individuals who are predisposed to mucosal infections. By uncovering potential beneficial commensal strategies with the host, as FAD-I appears to be, we may one day be able to exploit these strategies in protecting susceptible mucosal sites. FAD-I is a new discovery that warrants investigation into the possibility that it or its derivatives may provide a new direction into drug design that could be exploited locally to bolster Mother Nature's own defenses.

描述（由申请人提供）：据信，先天免疫系统是一种进化的古老反应，在出生时或生命的前几天都存在和功能。但是，共生细菌在“打开”先天免疫中起着作用。即，调节其反应，以及在生活中开始发生什么生命点，尚不清楚。我们实验室中的最新发现使我们推测口腔先天免疫反应的个体可能与口腔中的生物存在有关。 We recently discovered that Fusobacterium nucleatum, a ubiquitous Gram-negative bacterium of the human oral cavity, induces expression of epithelial cell derived human beta defensin -2 (hBD-2) and hBD-3 in normal oral epithelial cells (NHOECs), resulting in protection against invasion of Porphyromonas gingivalis, a major etiologic agent in periodontal破坏。广泛的生化和分子生物学工作已经鉴定出一种f.核外膜蛋白，该蛋白诱导这些抗菌和免疫调节性肽。我们将此蛋白称为fAD-I用于梭菌相关的防御蛋白诱导蛋白。此外，初步横截面数据表明，婴儿期唾液HBD水平明显低于年龄段的年龄组。我们怀疑与HBD诱导的年龄相关，以及其他可能的上皮细胞衍生的抗菌肽（AMP）与定殖和表达FAD-1表达F.核菌株的FAD-I的持续性相关。显然，我们需要通过（1）进行流行病学研究以研究整个年龄频谱的AMP水平，以建立整体，年龄分层和FAD-I相关分布，以了解更多有关这种动态的信息； （2）确定FAD-I对AMPS的电感特性及其随后对NHOEC保护的贡献，以及（3）通过采用分子和生化方法来确定HBD诱导中FAD-I的功能。通过更好地理解个人先天免疫AMP谱的个体基础，我们也许能够识别出易于粘膜感染的个体。通过FAD-I似乎是与宿主一起发现潜在的有益的共生策略，我们有一天可能能够利用这些策略来保护易感粘膜部位。 FAD-I是一个新发现，需要调查其或其衍生物可能为药物设计提供新方向的可能性，该方向可以在本地利用，以增强大自然母亲的防御能力。