Regulation of Human Beta-Defensins in Epithelia

描述（由申请人提供）：这是指导研究职业发展奖第二阶段教师过渡的提案，将为候选人提供先天免疫研究设计和实施方面的广泛知识，并将使她成功过渡到独立研究人员。该建议建立在候选人在口腔微生物学和口腔细菌与上皮细胞在先天防御中的相互作用的经验。需要验证的假设是，共生细菌和致病菌利用不同的信号传导途径诱导人类β -防御素，抗菌肽是先天免疫反应的组成部分。这项工作将集中在口腔粘膜和皮肤的共生和致病生物利用的独特途径和受体。初步数据表明，共生细菌使用MAPK途径，而病原体同时使用MAPK和NFkappaB诱导人β -防御素-2 （hBD-2）。RNAi技术将用于区分NFkappaB通路的两个分支，并研究参与人类a-防御素诱导的受体和其他信号通路成分。本提案还将研究牙龈卟啉单胞菌（一种侵袭性牙周病原体）参与人类β -防御素诱导的毒力因子，并确定其中的信号通路。这一建议的研究将导致更好地理解上皮细胞对病原和共生生物的不同反应方式。这项工作将有助于确定上皮细胞区分共生体和病原体并产生个体化反应的方式，以及不同的细胞表面受体如何与不同的细菌相互作用并发出人类β -防御素诱导的信号。这是先天免疫反应的一个重要方面，以前没有研究过。通过使用来自两个不同身体部位的细胞和细菌种类，结论将更加广泛和普遍意义。确定病原体刺激β -防御素的特定途径可能为开发刺激先天免疫反应的新治疗剂开辟道路。

DESCRIPTION (provided by applicant): This proposal for the Phase 2 Faculty Transition of a mentored research career development award will provide the candidate with the broad knowledge in the design and conduct of research in innate immunity and will lead to her successful transition to an independent researcher. The proposal builds on experience of the candidate in oral microbiology and in the interaction of oral bacteria with epithelial cells in innate defense. The hypothesis to be tested is that commensal and pathogenic bacteria utilize different signaling pathways in inducing human beta-defensins, antimicrobial peptides that are components of the innate immune response. This work will focus on the distinctive pathways and receptors utilized by commensal and pathogenic organisms from oral mucosa and skin. Preliminary data indicate that commensal bacteria use MAPK pathways, whereas pathogens use both MAPK and NFkappaB in inducing human beta-defensin-2 (hBD-2). RNAi technology will be utilized to differentiate the two arms of the NFkappaB pathway and to investigate receptors and other signaling pathway components involved in human a-defensin induction. This proposal will also investigate virulence factors of Porphyromonas gingivalis, an aggressive periodontal pathogen, involved in human beta-defensin induction, and identify signaling pathways involved. The studies of this proposal will lead to a better understanding of the way epithelial cells respond differently to pathogenic and commensal organisms. This work will help define the manner in which epithelial cells can distinguish commensals and pathogens and produce individualized responses, and how different cell-surface receptors interact with different bacteria and signal human beta-defensin induction. This is an important aspect of the innate immune response that has not been previously investigated. By using cells and bacterial species from two different body sites, the conclusions will be broader and more generally significant. Identifying specific routes pathogens take in stimulating beta-defensins may open the way for development of new therapeutic agents that stimulate the innate immune response.