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）：先天免疫系统是一种进化上古老的反应，被认为在出生时或生命的最初几天内就存在并发挥作用。然而，共生细菌在“开启”先天免疫方面发挥的作用；也就是说，调节它的反应，并且在生命的哪个个体发生点开始发生尚不清楚。我们实验室的最新发现使我们推测口腔先天免疫反应的个体发育可能与口腔中的定植微生物有关。我们最近发现，具核梭杆菌（一种人类口腔中普遍存在的革兰氏阴性细菌）可诱导正常口腔上皮细胞 (NHOEC) 上皮细胞来源的人β防御素 -2 (hBD-2) 和 hBD-3 的表达，从而导致防止牙龈卟啉单胞菌的侵入，牙龈卟啉单胞菌是牙周破坏的主要病原体。广泛的生化和分子生物学工作已经鉴定出具核梭杆菌外膜蛋白可诱导这些抗菌和免疫调节肽。我们将该蛋白称为 FAD-I，代表梭杆菌相关防御素诱导剂。此外，初步横断面数据表明，婴儿期唾液 hBD 水平显着低于老年组。我们怀疑与 hBD 诱导以及可能与其他上皮细胞衍生的抗微生物肽 (AMP) 的年龄相关的关联与表达 FAD-I 具核梭杆菌菌株的定植和持久性相关。显然，我们需要通过以下方式更多地了解这种动态：(1) 进行流行病学研究来调查整个年龄段的 AMP 水平，以建立总体、年龄分层和 FAD-I 相关的分布； (2) 确定 FAD-I 对 AMP 的诱导特性及其对 NHOEC 保护的后续贡献，以及 (3) 通过采用分子和生化方法来确定 hBD 诱导中的初步结构-功能关系，进一步表征 FAD-I 的功能。通过更好地了解个体先天免疫 AMP 谱的个体谱，我们也许能够识别出易受粘膜感染的个体。通过发现与宿主潜在的有益共生策略（如 FAD-I 所示），我们有一天可能能够利用这些策略来保护易受影响的粘膜部位。 FAD-I 是一项新发现，值得对其或其衍生物为药物设计提供新方向的可能性进行调查，这些药物设计可以在当地利用来增强大自然自身的防御能力。