Notch and TLRs Cross Paths in the Innate Immune System

描述（由申请人提供）：对病原体进行有效免疫反应的能力需要功能性先天免疫系统。先天免疫系统是抵御感染的第一道防线。toll样受体（Toll-like receptors， TLR）是一组存在于许多先天系统细胞中的膜结合受体，是驱动介导先天免疫反应的重要信号通路的分子。TLR信号通路成分被删除的小鼠研究强调了TLR的重要性。TLR信号的缺失严重损害了先天免疫反应，使宿主极易受到感染。在过去的一年中，包括我们自己的实验室在内的几个实验室已经表明，TLR信号除了激活NF-kB和MAPK信号通路外，还激活Notch信号通路。在这个应用中，我们提出Notch激活，一个新描述的TLR信号的新靶点，也影响对伯氏疏螺旋体的先天免疫反应。本应用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。这个应用程序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支持的科学家（Osborne）和发展中国家的合作者（Palaga）之间的研究伙伴关系。该提案的目的是扩展LMIC研究者和PI所做的重要和新颖的观察，改善LMIC站点的研究环境，并在PI的实验室培训LMIC学生。这项申请的首要目标是利用我们新颖的初步数据来促进两个实验室之间的科学合作和交流。虽然伯氏疏螺旋体不是泰国LMIC地区的地方性病原体，但伯氏疏螺旋体通过TLR2发出信号，这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研究者研究Notch信号在应对这些病原体中的作用提供一个框架。本应用程序的部分研究将在泰国曼谷的朱拉隆功大学进行，由塔纳帕特·帕拉加博士指导。本计划与家长补助金PO1 AG025531， Barbara A. Osborne， PI（7/1/06-6/30/11）相关联。

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.