Defining the cellular and molecular mechanisms regulating type III interferon responses

被称为细胞因子的蛋白质作为信使，无论是在动态平衡、炎症还是活动性感染期间，细胞都可以相互“交谈”。我的实验室研究的一个细胞因子家族，干扰素(IFN)，最早发现于1957年(第一型)，众所周知，它们在抑制病毒复制和传播方面发挥着关键作用。另一个抗病毒干扰素家族成员--III型干扰素(L)比I型干扰素晚46年才被发现，因此除了保护粘膜屏障上的上皮细胞外，还有许多基础性的问题尚未得到解答。我最近发表了一篇文章，指出新的人类免疫细胞类型直接对III型IFN做出反应，而III型IFN最终会影响它们对各种刺激的反应。此外，在III型干扰素受体生物学方面存在着主要的基础知识空白，特别是关于独特的III型干扰素受体亚单位干扰素-LambdaR1。在这个拟议的研究计划中，我和我的HQP将结合与免疫学、细胞生物学、生物化学、成像和分子生物学相关的多种方法和技术，以解决三个不同的短期目标和长期目标，以了解III型干扰素反应是如何在细胞和分子水平上调节的。在最初的5年里，我的HQP将在蛋白质和DNA水平上识别影响III型干扰素受体表达的信号。其次，我们将扩展我们以前的工作，以确定由III型IFN在免疫细胞中诱导的独特且可能独立于其抗病毒活性的新途径。最后，我们将可视化在III型IFN与其在个体免疫细胞中的受体结合后立即发生的情况。从我的研究计划中产生的知识将为一个研究很少的细胞因子家族提供新的见解，以回答关于III型干扰素信号和受体生物学的基本问题。这项拟议的工作还将揭示IFN下游的新的免疫和调节途径，包括家庭成员之间潜在的串扰。我们的工作还将通过在新兴免疫学领域对HQP进行各种尖端技术培训使加拿大受益，这将为他们提供适当的专业知识，使他们在未来的职业生涯中脱颖而出，成为科学领袖。

Proteins known as cytokines act as messengers for cells to `talk' to each other whether during periods of homeostasis, inflammation or an active infection. One family of cytokines my lab studies, interferons (IFNs), were discovered first in 1957 (type I), and are well-known for their critical role in inhibiting virus replication and spread. Another antiviral IFN family member, type III IFNs (IFN-lambdas (L)), were discovered 46 years later than type I IFNs, therefore multiple fundamental questions have yet to be answered outside of protecting epithelial cells at mucosal barriers. I recently published that new human immune cell types directly respond to type III IFNs, which ultimately affects their responses to various stimuli. In addition, major fundamental gaps in knowledge exist in type III IFN receptor biology, especially regarding the unique type III IFN receptor subunit IFN-LambdaR1. In this proposed research program, my HQP and I will combine multiple approaches and techniques related to immunology, cell biology, biochemistry, imaging, and molecular biology to address three distinct short-term objectives with the long-term goal to understand how type III IFN responses are regulated at the cellular and molecular level. In the first 5 years, my HQP will identify signals at the protein and DNA level that affect type III IFN receptor expression. Second, we will expand on our previous work to determine novel pathways induced by type III IFNs in immune cells that are unique and potentially independent of their antiviral activity. Lastly, we will visualize what happens immediately after type III IFNs bind their receptor in individual immune cells. Knowledge generated from my research program will provide novel insights into a much-understudied family of cytokines to answer fundamental questions about type III IFN signaling and receptor biology. The proposed work will also reveal new immunological and regulatory pathways downstream of IFNs, including potential crosstalk between family members. Our work will also benefit Canada through the training of HQP in various cutting-edge techniques within an emerging field of immunology that will provide them with the appropriate expertise to excel as scientific leaders in their future careers.