Evolutionary adaptations in the induction and control of acute inflammation

急性炎症诱导和控制的进化适应

• 批准号: RGPIN-2018-05768
• 负责人: Barreda, Daniel
• 金额: $ 4.74万
• 依托单位: University of Alberta
• 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=644696
• 关键词: Evolutionary; adaptations; induction; control; acute

The evolution of immune defense mechanisms remains the principal interest of my lab. Specifically, we focus on the fundamental contributions of white blood cells to the balance between pro-inflammatory and anti-inflammatory responses following infection. These are critical to antimicrobial defenses and maintenance of tissue integrity. Identification of novel evolutionary adaptations opened new doors to combat pathogens but in some cases also contributed to disease (e.g. autoimmunity, cancer). During the second installment of my NSERC Discovery program (2013-2018) my lab took significant strides towards defining the evolutionary contributions of phagocytes (well-conserved immune cell eaters) to the induction and control of acute inflammation. Development of novel comparative immunology tools for examination of cell function, and side-by-side comparisons of animal models that span large evolutionary distances (mammals, birds, bony fish, agnathans) identified key differences in the mechanisms that promote and control acute inflammation. This research supported the training of 46 highly qualified personnel (3 PDF, 6 PhD, 5 MSc, 26 UG, 1 RA, 5 Tech), whose excellence is reflected in 40 peer-reviewed publications, 69 awards including 1 PDF, 2 Vanier CGS (+1 ongoing nomination), 1 Julie Payette, 2 PGS-D, and 3 CGS-M NSERC Scholarships. Herein, I propose to use a combined molecular and cell biology approach that employs animal models and cell culture techniques to further dissect the evolution of the acute inflammatory response. Specifically, we will focus on two complementary but non-overlapping aims: 1) to dissect the evolving contributions of neutrophils to the transition between pro-inflammatory and resolution states at an infection site, and 2) to define the links between behavioural thermoregulation, immune activation, acute inflammation control, and the establishment of long-term immune memory. All major techniques, infrastructure, and a strong core of trainees are already in place in my lab, and are further supported through university facilities and collaborators. Our results have positive implications for the fundamental understanding of inflammation and offer new opportunities for the prevention of undesirable autoimmune and chronic inflammatory conditions. In addition, the proposed research has direct applicability to the aquaculture industry in the short-term (field applications expected in vaccination and drug-free health approaches within 5 years) and will help address a four-decade debate on the evolutionary origins of endothermy.

免疫防御机制的进化仍然是我实验室的主要兴趣。具体来说，我们关注的是白细胞在感染后促炎和抗炎反应之间的平衡中的基本贡献。这些对抗微生物防御和维持组织完整性至关重要。发现新的进化适应为对抗病原体打开了新的大门，但在某些情况下也导致了疾病（如自身免疫、癌症）。在我的NSERC发现计划的第二部分（2013-2018）中，我的实验室在定义吞噬细胞（保存良好的免疫细胞吞噬者）对诱导和控制急性炎症的进化贡献方面取得了重大进展。用于检查细胞功能的新型比较免疫学工具的发展，以及跨越大进化距离的动物模型（哺乳动物，鸟类，硬骨鱼，agnathans）的并排比较，确定了促进和控制急性炎症机制的关键差异。这项研究支持了46名高素质人才的培训（3名PDF， 6名博士，5名硕士，26名UG， 1名RA， 5名Tech），他们的卓越表现体现在40篇同行评审的出版物中，69个奖项，包括1个PDF， 2个Vanier CGS（+1个正在提名），1个Julie Payette， 2个PGS-D和3个CGS- m NSERC奖学金。在此，我建议使用结合分子和细胞生物学的方法，采用动物模型和细胞培养技术来进一步剖析急性炎症反应的演变。具体来说，我们将关注两个互补但不重叠的目标：1)解剖中性粒细胞在感染部位促炎和消退状态之间转变的进化贡献；2)定义行为体温调节、免疫激活、急性炎症控制和建立长期免疫记忆之间的联系。在我的实验室里，所有的主要技术、基础设施和强大的核心学员都已经到位，并得到了大学设施和合作者的进一步支持。我们的结果对炎症的基本理解具有积极意义，并为预防不良自身免疫和慢性炎症状况提供了新的机会。此外，拟议的研究在短期内可直接适用于水产养殖业（预计在5年内用于疫苗接种和无药物保健方法的实地应用），并将有助于解决关于恒温动物进化起源的四十年辩论。