Defining the cellular and molecular mechanisms regulating type III interferon responses

被称为细胞因子的蛋白质充当细胞的信使，无论是在体内平衡、炎症还是活动性感染期间，它们都能相互“交谈”。我实验室研究的一个细胞因子家族，干扰素（IFN），于1957年首次发现（I型），并以其在抑制病毒复制和传播中的关键作用而闻名。另一种抗病毒IFN家族成员，III型IFN（IFN-IFN（L））比I型IFN晚46年被发现，因此除了保护粘膜屏障处的上皮细胞之外，还有许多基本问题尚未得到回答。我最近发表了新的人类免疫细胞类型直接响应III型IFN，这最终影响了它们对各种刺激的反应。此外，在III型IFN受体生物学方面存在主要的基本知识空白，特别是关于独特的III型IFN受体亚基IFN-LambdaR 1。在这个拟议的研究计划中，我和我的HQP将结合联合收割机与免疫学，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与长期目标，以了解III型IFN反应是如何在细胞和分子水平上调节。在前5年，我的HQP将在蛋白质和DNA水平上识别影响III型IFN受体表达的信号。其次，我们将扩大我们以前的工作，以确定新的途径诱导的III型干扰素在免疫细胞是独特的，可能独立于其抗病毒活性。最后，我们将可视化III型IFN结合单个免疫细胞中的受体后立即发生的情况。从我的研究计划产生的知识将提供新的见解到一个研究不足的细胞因子家族，以回答有关III型IFN信号和受体生物学的基本问题。拟议的工作还将揭示IFN下游新的免疫和调节途径，包括家族成员之间的潜在串扰。我们的工作还将通过在新兴的免疫学领域对HQP进行各种尖端技术的培训，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成为科学领导者。

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.