Cytokines and host defence peptides: Mechanisms of immunomodulation

炎症是有效免疫的基本要素。然而，这种生物学过程必须是自我限制或调节的，以维持健康状态（免疫稳态）。被称为细胞因子的分子协调免疫反应，并在需要时介导炎症。细胞因子介导的炎症由不同的细胞机制精心调节/控制以维持免疫稳态。 过去三十年的研究表明，被称为阳离子宿主防御肽（CHDP）的内源性分子在炎症调节中非常重要。CHDP具有广泛的免疫相关功能，并有助于免疫稳态。CHDP可以根据细胞环境介导促炎和抗炎反应，并选择性地调节炎症过程。Cathelicidins和Defensins是哺乳动物中CHDP的两个最具特征的组。CHDP对粘膜表面（即衬在体腔内并覆盖内脏器官表面的区域）的精氨酸介导的细胞反应的影响仍有待充分阐明。知识差距：CHDP可以调节细胞因子介导的炎症，但其发生的潜在机制（即蛋白质变化和细胞信号传导）尚未完全了解。此外，细胞因子如何改变CHDP表达仍不清楚。 我的NSERC DG计划的长期愿景是确定CHDP调节姜黄素诱导的反应，调节炎症和维持免疫稳态的机制。我的DG研究将增加对CHDP和细胞因子相互作用的基础生物学的理解。短期目标：最近，我已经表明，CHDP cathelicidin LL-37选择性地调节血液来源的细胞和上皮细胞（构成组织的结构细胞）中的精氨酸介导的炎症。我的5年短期目标是研究LL-37如何改变细胞反应和信号传导机制，在两种细胞因子（IL-17和IFN-γ）的存在下，使用两种不同的细胞类型。我还旨在定义控制LL-37介导的促炎反应与抗炎反应的分子过程。长期目标是扩大我的研究范围，包括其他CHDP，如β-防御素，并全面了解CHDP如何改变尼古丁诱导的炎症。我最近发现，一些细胞因子可以改变某些CHDP的表达谱。因此，进一步的长期目标将是关注细胞因子和CHDP之间的反馈回路（相互作用），其允许它们控制彼此在不同细胞类型中的丰度。影响：我的计划将定义CHDP免疫调节功能中的受体，蛋白质靶点和途径。这将有助于详细研究维持炎症稳态的动态过程。我的实验室提供跨学科环境的培训，包括免疫学和系统生物学，生命科学的快速发展领域。

Inflammation is a fundamental element of efficient immunity. However, this biological process must be self-limiting or regulated to maintain a healthy state (immune homeostasis). Molecules known as cytokines orchestrate immune responses and mediate inflammation when required. Cytokine-mediated inflammation is meticulously regulated / controlled by different cellular mechanisms to maintain immune homeostasis. Studies in the last three decades indicate that endogenous molecules known as cationic host defence peptides (CHDP) are important in the regulation of inflammation. CHDP have a wide range of immunity-related functions and contribute to immune homeostasis. CHDP can mediate both pro- and anti-inflammatory responses depending on the cellular environment, and selectively regulate the inflammatory process. Cathelicidins and Defensins are the two best characterized groups of CHDP in mammals. The effect of CHDP on cytokine-mediated cellular responses at mucosal surfaces (i.e. areas that line body cavities and cover the surface of internal organs) remains to be fully elucidated. Gap in knowledge: CHDP can modulate cytokine mediated-inflammation, but the underlying mechanisms by which this occurs (i.e. protein changes and cell signaling) are not completely understood. Moreover, how cytokines may change CHDP expression remains undefined.  The long term vision of my NSERC DG program is to define mechanisms by which CHDP modulate cytokine-induced responses, to regulate inflammation and maintain immune homeostasis. My DG research will add to the understanding of the fundamental biology in the interplay of CHDP and cytokines. Short term objectives: Recently, I have shown that CHDP cathelicidin LL-37 selectively regulates cytokine-mediated inflammation in blood-derived cells and in epithelial cells (structural cells that make up tissues). My 5-yr short term objectives are to examine how LL-37 alters cellular responses and signaling mechanisms in the presence of two cytokines (IL-17 and IFN-gamma) using two different cell types. I also aim to define molecular processes that control the pro- vs anti-inflammatory responses mediated by LL-37. The long term goal is to expand my research scope to include other CHDP such as ß-defensins, and to comprehensively understand how CHDP alter cytokine-induced inflammation. I have recently shown that some cytokines can change the expression profile of certain CHDP. Thus, a further long term goal will be to focus on the feedback loop (interplay) between cytokines and CHDP that allows them to control one another's abundance in different cell types. Impact: My program will define the receptors, protein targets and pathways in the immunomodulatory functions of CHDP. This will facilitate detailed investigation of the dynamic processes in maintaining inflammatory homeostasis. My lab provides training in an interdisciplinary environment, including Immunology & Systems Biology, rapidly growing areas of life sciences.