Cytokines and host defence peptides: Delineating molecular mechanisms regulating inflammation

细胞因子和宿主防御肽：描述调节炎症的分子机制

• 批准号: 435549-2013
• 负责人: Mookherjee, Neeloffer
• 金额: $ 3.64万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=660106
• 关键词: Cytokines; host; defence; peptides; Delineating

Molecules known as cytokines are critical in orchestrating immune responses. An important element of immunity is the process of inflammation, which is normally self-limiting and tightly regulated. A breakdown in the regulation of this process results in inappropriately excessive and sustained inflammation. A common element in inflammation is the elevated levels of certain cytokines. Abnormally elevated levels of some of these cytokines are known to amplify the process of inflammation. Recent studies have shown that small natural peptides, known as host defence peptides (HDPs), may be important in regulation of inflammation. Our previous research has shown that these HDPs can exhibit an overall anti-inflammatory effect. However, how HDPs regulate cytokine induced cellular responses in inflammation is poorly understood. Therefore, our research focus is to understand how HDPs alter or regulate cytokine-activated processes in inflammation. The short term i.e. 5 year research goal is to focus on a well defined human HDP, known as cathelicidin LL-37. We have previously shown that LL-37 can suppress inflammation in the presence of an infection or tissue injury. However, the function of LL-37 in the presence of inflammatory cytokines is not understood. We will study the molecular processes of how LL-37 may alter the effect of two inflammatory cytokines in our 5 year goal. In order to facilitate our research objectives, we will determine the proteins and enzymes that are activated by inflammatory cytokines, and how these responses change in the presence of HDPs such as LL-37. We will study these molecular mechanisms in two different cell types, in immune cells and in structural stromal cells which are the connective tissue cells of any organ. Our long term overall goal is to determine the effects of HDPs in inflammatory cytokine-induced cellular processes. Overall, our studies will provide a broader understanding of the impact of the endogenous HDP molecules on cellular processes that are important for regulation of inflammation.****

被称为细胞因子的分子在协调免疫反应中至关重要。免疫的一个重要因素是炎症过程，这通常是自限性和严格调节的。这一过程的调节中断会导致不适当的过度和持续的炎症。炎症中的一个常见因素是某些细胞因子水平升高。已知这些细胞因子中的一些细胞因子的水平异常升高会放大炎症过程。最近的研究表明，小的天然肽，称为宿主防御肽（HDPs），可能是重要的炎症调节。我们以前的研究表明，这些HDPs可以表现出整体抗炎作用。然而，HDP如何调节炎症中细胞因子诱导的细胞反应知之甚少。因此，我们的研究重点是了解HDPs如何改变或调节炎症中的精氨酸激活过程。短期（即5年）研究目标是集中在一种明确的人类HDP，称为凯萨林菌素LL-37。我们之前已经证明，LL-37可以在感染或组织损伤的情况下抑制炎症。然而，LL-37在炎性细胞因子存在下的功能尚不清楚。我们将在我们的5年目标中研究LL-37如何改变两种炎性细胞因子作用的分子过程。为了促进我们的研究目标，我们将确定由炎性细胞因子激活的蛋白质和酶，以及这些反应在HDP（如LL-37）存在下如何变化。我们将在两种不同的细胞类型中研究这些分子机制，即免疫细胞和结构基质细胞（任何器官的结缔组织细胞）。我们的长期总体目标是确定HDPs在炎症性细胞过程中的作用。总的来说，我们的研究将为内源性HDP分子对炎症调节重要的细胞过程的影响提供更广泛的理解。