Cellular and molecular mechanisms of inflammatory T cell regulation.

免疫系统的T细胞迅速增殖，以应对细菌、病毒和肿瘤。它们通过直接杀死受感染的细胞或通过吸引其他附属免疫细胞促进炎症来协调身体对病原体和癌症的反应。由于T细胞可以在感染后以惊人的速度繁殖，并且它们产生许多可能对身体有害的抗微生物和抗病毒分子，因此严格控制T细胞的反应是至关重要的。因此，T细胞在其表面表达负信号受体。负表面受体的触发会激活T细胞内的蛋白质信号通路，导致T细胞死亡或降低其促炎功能。这样，一旦感染被清除，免疫系统就会避免过度的、不适当的炎症。这项研究计划的主要目标是确定负信号受体下游的分子通路。我们之前已经确定了一种名为BAT3的分子，它通过负向受体TIM-3停止信号传递。因此，BAT3促进了T细胞驱动的炎症。然而，关于BAT3在T细胞中的功能，我们仍然有很多需要了解的地方。使用分子和细胞生物学方法的组合，我和我的团队将定义BAT3运作的分子途径。然后，我们将确定与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活细胞中BAT3与其他分子的结合强度。综上所述，NSERC程序将使我们能够更好地理解介导T细胞反应负调控的分子信号。这些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。该NSERC计划还将确保培训未来高素质的学生、博士后研究员和研究助理，掌握与基础研究相关的技术。

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.**