Notch and TLRs Cross Paths in the Innate Immune System

Notch 和 TLR 在先天免疫系统中交叉

基本信息

批准号：
7943669
负责人：
BARBARA A OSBORNE
金额：
$ 5.96万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-20 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943669
关键词：
Address Antigens Award Biology Borrelia Borrelia burgdorferi Cell physiology Cells Cellular biology Collaborations Collection Complement Data Development Doctor of Philosophy Drug Delivery Systems Educational process of instructing Electronic Mail Environment Experimental Autoimmune Encephalomyelitis Faculty Flow Cytometry Fostering Funding Generations Germany Goals Grant Head Health Home environment Host Defense Human Immune response Immune system Immunology In Vitro Infection Inflammatory Institution Interleukin-6 Japan Journals Knowledge Laboratories Learning Leptospira interrogans Leptospirosis Letters Life Link MAP Kinase Gene Massachusetts Mediating Membrane Mentors Microbiology Mission Mus NF-kappa B Nature New England Notch Signaling Pathway Occupations Outcome Parents Pathway interactions Play Positioning Attribute Process Production Reagent Receptor Signaling Regulatory T-Lymphocyte Research Research Personnel Rewards Role Scientist Seminal Series Signal Pathway Signal Transduction Site Students System T-Cell Activation T-Lymphocyte TLR2 gene TLR4 gene Technology Technology Transfer Testing Th1 Cells Thailand Time Toll-like receptors Training Travel Universities Visit Work Writing cytokine defense response design experience immune function in vivo inhibitor/antagonist insight interest knockout animal lecturer lymphocyte proliferation macrophage meetings notch protein novel overexpression parent grant pathogen post-doctoral training professor programs public health relevance receptor binding research study response secretase skills symposium tool

项目摘要

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.

描述（由申请人提供）：对病原体有效反应的能力需要一种功能性的先天免疫系统。先天免疫系统提供了针对感染的第一道防线。 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反应的重要信号通路的分子。通过使用TLR信号通路组件的小鼠的研究，TLR的重要性强调了。 TLR信号的丧失严重损害了先天免疫反应，并使宿主极易受到感染的影响。在过去的一年中，包括我们自己的几个实验室，还表明，除了激活NF-KB和MAPK途径外，TLR信号传导还激活了Notch信号通路。在此应用中，我们建议Notch激活是TLR信号传导的新靶标，也影响了先天免疫对病原体Borrelia burgdorferi的反应。本应用程序中提出的实验旨在揭示TLR信号导致Notch激活的机制，并可能建议调节免疫反应的新型药物靶标。该应用程序的第二个也同样重要的组成部分是促进NIH支持的科学家（Osborne）与发展中国家合作者（Palaga）之间的研究伙伴关系。该提案的目的旨在扩展LMIC研究者和PI的重要和新颖的观察结果，并在LMIC站点增强研究环境，并在PI实验室培训LMIC学生。该应用程序的总体目标是利用我们的新型初步数据来促进两个实验室之间的科学协作和交流。尽管伯氏菌不是LMIC部位的病原体，但泰国，通过TLR2信号是TLR2的信号，TLR2是泰国许多病原体使用的信号传导途径。我们在本应用中提出的研究将为LMIC研究者提供一个框架，以研究Notch信号对这些病原体的作用。该申请中的研究将部分在泰国曼谷朱拉隆科大学进行，并由Tanapat Palaga博士执导。该项目链接到父母授予PO1 AG025531，Barbara A. Osborne，PI（7/1/06-6/30/11）。公共卫生相关性：该应用程序的目的将描述介导对病原体的先天免疫反应的新型机制。先天免疫反应对于大多数病原体的清除至关重要。因此，提供有关这些过程的洞察力的研究对人类健康有很大影响。该申请将与泰国曼谷Chulalongkorn University的LMIC研究员一起进行，并将帮助LMIC机构的研究工作和培训。