Complement activation causes energy and metabolism changes in endothelial cells.

补体激活导致内皮细胞能量和代谢发生变化。

• 批准号: RGPIN-2019-06477
• 负责人: Licht, Christoph
• 金额: $ 2.33万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684213
• 关键词: Complement; activation; causes; energy; metabolism

***The immune system is a network of proteins, cells, tissues, and organs*that protect the body against invaders (e.g., viruses, bacteria). Part of the*system's first line of defense is the complement system, which helps clear*invaders and damaged cells out of the body. When the clearance of such*invaders/damaged cells is needed, the complement cascade is activated,*resulting in the tagging of damaged cells rendering them target of clean up via*white blood cells, or in the formation of pores in the surface of invading*cells, causing their destruction. The inner lining of blood vessels the*endothelial cells is in constant contact with the complement system, but it*has regulators on its surface to prevent the spontaneous activation of*complement when and where it is not needed. Though normally tightly regulated, genetic*defects or the presence of inhibiting autoantibodies can impair complement*control, and spontaneous activation can happen, which can attack the normal,*unaffected endothelial cells. The mechanisms these cells engage to allow for*evasion of complement attack thus allowing for survival are currently only poorly*understood.******Our group has previously established a protocol allowing for complement*activation on endothelial cells. In this model, endothelial cells lose their*ability to migrate and are depleted of their energy stores (mainly*mitochondria, the powerhouse of the cell), but they do not die even after a*long exposure (6h). We here propose to determine the survival mechanisms being*engaged in endothelial cells during complement attack, as well as to determine*the metabolic/energetic changes occurring in these cells ultimately allowing them*to evade complement attack and survive. Consequently, we also aim to determine*the “tipping point” of these defense mechanisms, i.e. the factors that might*ultimately tip the cell's machinery to no longer withstand complement attack*and commit to clearance of these damaged cells that would otherwise harm the*organism.******We anticipate to find various ways*endothelial cells try to hold a balanced and functional intracellular state*while they are under complement attack, including inhibiting the machinery the*cells use to kill highly damaged cells, depending more on alternative sources*of energy (other than mitochondria), and trying to remove the pore from their*surfaces. Also, once we have determined the players in these mechanisms, we can*inhibit their activity used during survival state, when we expect to see the*cells commit to dying faster than if these mechanisms were active.******As the complement system is ubiquitously present throughout the body, we expect that results generated in the here proposed research*project will have the potential to generate fundamental new insights into*cell/tissue survival mechanisms of virtually all tissue/organ systems of the*body, not only the endothelial cells.*********

***免疫系统是一个由蛋白质、细胞、组织和器官组成的网络*，保护身体免受入侵者（例如病毒、细菌）的侵害。该系统第一道防线的一部分是补体系统，它有助于清除体内的入侵者和受损细胞。当需要清除此类*入侵者/受损细胞时，补体级联被激活，*导致受损细胞被标记，使它们成为通过*白细胞清除的目标，或者在入侵*细胞表面形成孔，导致其被破坏。血管内皮细胞与补体系统持续接触，但其表面有调节器，以防止补体在不需要的时间和地点自发激活。尽管通常受到严格调控，但遗传*缺陷或抑制性自身抗体的存在会损害补体*控制，并且可能发生自发激活，从而攻击正常的、*未受影响的内皮细胞。目前，人们对这些细胞逃避补体攻击从而得以生存的机制知之甚少。******我们的小组之前已经建立了一种允许补体*激活内皮细胞的方案。在此模型中，内皮细胞失去*迁移能力并耗尽其能量储存（主要*线粒体，细胞的动力源），但即使在长时间暴露（6小时）后它们也不会死亡。我们在这里建议确定补体攻击期间*参与内皮细胞的生存机制，以及确定*这些细胞中发生的代谢/能量变化，最终允许它们*逃避补体攻击并生存。因此，我们还旨在确定*这些防御机制的“临界点”，即可能*最终使细胞机制不再承受补体攻击*并致力于清除这些可能损害*生物体的受损细胞的因素。******我们期望找到各种方法*内皮细胞在受到补体攻击时尝试保持平衡和功能性的细胞内状态*，包括抑制*细胞的机制 用于杀死高度受损的细胞，更多地依赖替代能源（线粒体除外），并试图从其表面去除毛孔。此外，一旦我们确定了这些机制中的参与者，我们就可以*抑制它们在生存状态下使用的活动，当我们期望看到*细胞比这些机制活跃时更快地死亡时。******由于补体系统普遍存在于全身，我们预计这里提出的研究*项目中产生的结果将有可能对几乎所有组织/器官的*细胞/组织生存机制产生基本的新见解 *身体的系统，不仅仅是内皮细胞。*********