Cytokines and host defence peptides: Mechanisms of immunomodulation

炎症是有效免疫的基本要素。然而，这一生物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，并在需要时调节炎症。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，内源性分子阳离子宿主防御肽(CHDP)在调节炎症过程中发挥着重要作用。CHDP具有广泛的免疫相关功能，有助于免疫动态平衡。CHDP可根据细胞环境调节促炎和抗炎反应，并选择性地调节炎症过程。放线菌素和防御素是哺乳动物中最具特征的两类CHDP。CHDP对粘膜表面(即体腔和内脏表面覆盖区域)细胞因子介导的细胞反应的影响尚未完全阐明。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)尚不完全清楚。此外，细胞因子如何改变CHDP的表达仍未确定。我的NSERC DG计划的长期愿景是定义CHDP调节细胞因子诱导的反应、调节炎症和维持免疫动态平衡的机制。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，我已经证明CHDP天青素LL-37选择性地调节血源性细胞和上皮细胞(构成组织的结构细胞)中的细胞因子介导的炎症。我的5年短期目标是研究在两种不同细胞类型的两种细胞因子(IL-17和干扰素-γ)存在的情况下，LL-37如何改变细胞反应和信号机制。我的目标也是定义控制由LL-37介导的前VS抗炎反应的分子过程。我们的长期目标是扩大我的研究范围，包括其他CHDP，如防御素，并全面了解CHDP如何改变细胞因子诱导的炎症。我最近发现，某些细胞因子可以改变某些CHDP的表达谱。因此，另一个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)，使它们能够控制不同细胞类型中彼此的丰度。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，这是生命科学中迅速增长的领域。

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.