Notch and TLRs Cross Paths in the Innate Immune System

描述（由申请人提供）：对病原体产生有效免疫应答的能力需要功能性先天免疫系统。先天免疫系统是抵抗感染的第一道防线。Toll样受体（TLR）是在先天系统的许多细胞上发现的膜结合受体的集合，是驱动介导先天免疫应答的重要信号传导途径的分子。TLR的重要性通过使用TLR信号通路的组分被删除的小鼠的研究而被强调。TLR信号传导的丧失严重损害先天免疫应答并使宿主对感染高度易感。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表明，TLR信号除了激活NF-κ B和MAPK通路外，还激活Notch信号通路。在本申请中，我们提出Notch激活，一种新描述的TLR信号传导的新靶点，也影响对病原体伯氏疏螺旋体的先天免疫应答。本申请中提出的实验旨在阐明TLR信号传导导致Notch活化的机制，并可能提出用于调节免疫应答的新药物靶标。 该应用程序的第二个同样重要的组成部分是促进NIH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调查员和PI所做的重要和新颖的观察，并改善LMIC现场的研究环境，以及在PI实验室培训LMIC学生。该应用程序的首要目标是利用我们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LMIC站点（泰国）特有的病原体，但疏螺旋体通过TLR 2（泰国特有的许多病原体使用的信号传导途径）发出信号。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信号在响应这些病原体中的作用。 本申请中的研究部分将在泰国曼谷朱拉隆功大学进行，并由Tanapat Palaga博士指导。本项目与母基金PO 1 AG 025531，Barbara A. Osborne，PI（7/1/06-6/30/11）. 公共卫生相关性：本申请的目的将描述介导对病原体的先天免疫应答的新机制。先天免疫应答对于清除大多数病原体至关重要。因此，深入了解这些过程的研究对人类健康有很大的影响。该申请将与泰国曼谷朱拉隆功大学的LMIC研究员一起进行，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.