Notch and TLRs Cross Paths in the Innate Immune System

描述(由申请者提供)：对病原体进行有效免疫反应的能力需要一个功能正常的天然免疫系统。先天免疫系统是抵御感染的第一道防线。Toll样受体(Toll-like Receptor，TLR)是一组膜结合受体，存在于天然系统的许多细胞中，是驱动重要信号通路的分子，介导天然免疫反应。TLRs的重要性通过使用TLR信号通路组件缺失的小鼠的研究而突显出来。TLR信号的缺失严重损害了先天免疫反应，使宿主对感染高度敏感。在过去的一年里，包括我们自己的实验室在内的几个实验室已经证明，TLR信号除了激活NF-kB和MAPK通路外，还激活Notch信号通路。在这个应用中，我们认为Notch激活，一个新描述的TLR信号的新靶点，也影响了对病原体伯氏疏螺旋体的先天免疫反应。本申请中提出的实验旨在揭示TLR信号导致Notch激活的机制，并可能为调节免疫反应提供新的药物靶点。这项申请的第二个同样重要的组成部分是促进美国国立卫生研究院资助的科学家(奥斯本)和发展中国家的合作者(帕拉加)之间的研究伙伴关系。这项建议的目的是扩大LMIC调查员和PI所做的一项重要和新颖的观察，并改善LMIC现场的研究环境，以及在PI的实验室培训LMIC学生。这项应用的首要目标是利用我们的新的初步数据来促进两个实验室之间的科学合作和交流。虽然疏螺旋体不是泰国LMIC地点特有的病原体，但疏螺旋体通过TLR2信号传递信号，TLR2是泰国许多地方性病原体使用的信号通路。我们在本申请中提出的研究将为LMIC研究者提供一个框架，以研究Notch信号在这些病原体反应中的作用。这项申请的研究将在泰国曼谷的朱拉隆功大学进行，由Tanapat Palaga博士指导。该项目与家长资助PO1 AG025531，Barbara A.Osborne，Pi(7/1/06-6/30/11)相关联。 与公共卫生相关：本申请的目的将描述调节对病原体的先天免疫反应的新机制。先天免疫反应是清除大多数病原体的关键。因此，对这些过程提供洞察的研究对人类健康具有很高的影响。这项申请将与泰国曼谷朱拉隆功大学的一名LMIC调查员一起进行，并将有助于LMIC机构的研究工作和学生培训。

DESCRIPTION (provided by applicant): The ability to mount an effective immune response to pathogens requires a functional innate immune system. The innate immune system provides the first line of defense against infection. Toll-like receptors (TLR), a collection of membrane bound receptors found on many cells of the innate system, are molecules that drive important signaling pathways mediating the innate immune response. The importance of TLRs is highlighted by studies employing mice where components of the TLR signaling pathway are deleted. Loss of TLR signaling severely compromises innate immune responses and renders the host highly susceptible to infection. During the past year, several laboratories, including our own, have shown that TLR signaling, in addition to activating NF-kB and MAPK pathways, also activates the Notch signaling pathway. In this application, we propose that Notch activation, a newly described and novel target of TLR signaling, also influences innate immunes responses to the pathogen Borrelia burgdorferi. The experiments proposed in this application are designed to unravel the mechanism by which TLR signaling leads to Notch activation and may suggest novel drug targets for modulating immune responses. A second and equally important component of this application is to foster research partnerships between NIH-supported scientists (Osborne) and collaborators in the developing world (Palaga). The aims of this proposal are designed to extend an important and novel observation made by the LMIC investigator and the PI and to enhance research environment at the LMIC site as well as train an LMIC student in the PI's laboratory. The overarching goal of this application is to utilize our novel preliminary data to promote scientific collaboration and exchange between the two laboratories. Although Borrelia is not a pathogen endemic to the LMIC site, Thailand, Borrelia signals through TLR2, a signaling pathway used by many pathogens endemic in Thailand. Our studies proposed in this application will provide a framework for the LMIC investigator to investigate the role of Notch signaling in response to these pathogens. The research in this application will be conducted, in part, at Chulalongkorn University, Bangkok, Thailand and directed by Dr. Tanapat Palaga. This project is linked to parent grant PO1 AG025531, Barbara A. Osborne, PI (7/1/06-6/30/11). PUBLIC HEALTH RELEVANCE: The aims of this application will describe novel mechanisms that mediate the innate immune response to pathogens. Innate immune responses are critical for the clearance of most pathogens. Therefore studies that provide insight into these processes have high impact on human health. This application will be conducted in conjunction with an LMIC investigator at Chulalongkorn University in Bangkok, Thailand and will aid research efforts and training of students at the LMIC institution.