Cellular and molecular mechanisms of inflammatory T cell regulation.

炎症 T 细胞调节的细胞和分子机制。

• 批准号: RGPIN-2015-03665
• 负责人: Rangachari, Manu
• 金额: $ 2.33万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=707982
• 关键词: Cellular; molecular; mechanisms; inflammatory; cell

T cells of the immune system proliferate rapidly in response to bacteria, viruses and tumors. They co-ordinate the body's response to pathogens and cancer by either killing infected cells directly, or by attracting other accessory immune cells to promote inflammation. As T cells can multiply at a dramatic rate in response to infection, and as they produce many antimicrobial and antiviral molecules that can be toxic to the body in large amounts, it is crucial that T cell responses be tightly controlled. T cells thus express negative signaling receptors on their surface. Triggering of negative surface receptors leads to the activation of protein signaling pathways within the T cell, causing them to either die or to reduce their pro-inflammatory functions. In this way, the immune system avoids excessive, inappropriate inflammation once an infection has been cleared.  The main goal of this research program is to identify molecular pathways downstream of negative signaling receptors. We have previously identified a molecule, Bat3, that stops signaling via the negative receptor Tim-3. Bat3 thus promotes T cell-driven inflammation. However, there is much that we still need to learn about the function of Bat3 in T cells. Using a combination of molecular and cell biological approaches, my team and I will define the molecular pathways by which Bat3 operates. We will then identify other T cell proteins that bind to Bat3 and that affect these pathways. We will then use cutting edge technology to determine how specific T cell growth factors can influence the strength of binding of Bat3 to other molecules in living cells. Taken together, this NSERC program will allow us to better understand the molecular signals that mediate negative regulation of T cell responses. The findings will have direct implications for future studies aimed at creating a molecular map of protein interactions that are relevant to maintaining proper function of the immune system. This NSERC program will also ensure the training of future highly qualified students, postdoctoral fellows and research assistants in techniques relevant to fundamental research.

免疫系统中的T细胞在面对细菌、病毒和肿瘤时迅速增殖。它们协调机体对病原体和癌症的反应，要么直接杀死受感染的细胞，要么吸引其他辅助免疫细胞促进炎症。由于T细胞可以以惊人的速度繁殖以应对感染，并且由于它们产生许多抗菌和抗病毒分子，这些分子大量产生可能对身体有毒，因此严格控制T细胞反应至关重要。因此，T细胞在其表面表达负信号受体。负表面受体的触发导致T细胞内蛋白质信号通路的激活，导致它们死亡或降低其促炎功能。通过这种方式，一旦感染被清除，免疫系统就会避免过度的、不适当的炎症。本研究计划的主要目标是确定负信号受体下游的分子途径。我们之前已经确定了一种分子Bat3，它可以停止通过负受体Tim-3传递信号。因此，Bat3促进了T细胞驱动的炎症。然而，关于T细胞中Bat3的功能，我们还有很多需要了解的地方。结合分子生物学和细胞生物学的方法，我和我的团队将定义Bat3运作的分子途径。然后，我们将识别与Bat3结合并影响这些途径的其他T细胞蛋白。然后，我们将使用尖端技术来确定特定的T细胞生长因子如何影响Bat3与活细胞中其他分子的结合强度。总之，这个NSERC项目将使我们能够更好地理解介导T细胞反应负调节的分子信号。这一发现将对未来的研究产生直接影响，这些研究旨在创建与维持免疫系统正常功能相关的蛋白质相互作用的分子图谱。国家科学研究委员会的这项计划还将确保培养未来高素质的学生、博士后和研究助理，掌握与基础研究相关的技术。