Regulation of Human Beta-Defensins in Epithelia

描述（由申请人提供）：这一建议的第二阶段教师过渡的指导研究职业发展奖将提供候选人在先天免疫研究的设计和进行广泛的知识，并将导致她成功过渡到一个独立的研究人员。该提案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相互作用的经验基础上。待测试的假设是，肠道和病原菌利用不同的信号传导途径诱导人β-防御素，抗微生物肽，其是先天免疫应答的组分。这项工作将集中在独特的途径和受体所利用的口腔粘膜和皮肤的寄生虫和病原生物体。初步数据表明，大肠杆菌使用MAPK途径，而病原体使用MAPK和NF κ B诱导人β-防御素-2（hBD-2）。RNAi技术将用于区分NF κ B通路的两个分支，并研究参与人α-防御素诱导的受体和其他信号通路组分。这项提案还将调查牙龈卟啉单胞菌，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，并确定参与的信号通路。该提案的研究将导致更好地了解上皮细胞对病原体和寄生虫生物体的不同反应方式。这项工作将有助于确定上皮细胞可以区分细菌和病原体并产生个性化反应的方式，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物种，结论将更广泛，更普遍。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.