Regulation of Human Beta-Defensins in Epithelia

描述(由申请人提供)：这项关于指导研究职业发展奖第二阶段教师过渡的建议将为候选人提供设计和进行先天免疫研究的广泛知识，并将导致她成功过渡到一名独立研究人员。该提案基于候选人在口腔微生物学以及口腔细菌与上皮细胞在天然防御中的相互作用方面的经验。需要检验的假设是，共生细菌和致病细菌在诱导人类β-防御素方面利用不同的信号通路，β-防御素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病原体利用的独特的途径和受体。初步数据表明，共生细菌使用MAPK途径，而病原体在诱导人β-防御素-2(HBD-2)时同时使用MAPK和NFkappaB。RNAi技术将被用来区分NFkappaB通路的两个臂，并研究参与人类α-防御素诱导的受体和其他信号通路组件。这项建议还将调查牙龈卟啉单胞菌的毒力因素，这是一种侵袭性牙周病原体，参与人类β-防御素的诱导，并确定相关的信号通路。对这一提议的研究将有助于更好地理解上皮细胞对病原生物和共生生物的不同反应方式。这项工作将有助于定义上皮细胞区分共生体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，以前还没有被研究过。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，更具普遍意义。确定病原体刺激β-防御素的具体途径可能会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.