Complement activation causes energy and metabolism changes in endothelial cells.

*免疫系统是由蛋白质、细胞、组织和器官组成的网络*，它们保护身体免受入侵者(如病毒、细菌)的侵袭。补体系统是该系统第一道防线的一部分，它可以帮助清除人体内的入侵者和受损细胞。当需要清除这种入侵者/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*细胞的表面形成气孔，导致它们被破坏。血管的内层内皮细胞与补体系统持续接触，但它的表面有调节器，以防止补体在不需要的时候自发激活。尽管正常情况下受到严格控制，但遗传缺陷或抑制性自身抗体的存在可能会削弱补体*控制，并可能发生自发激活，这可能会攻击正常的、未受影响的内皮细胞。这些细胞参与的机制允许逃避补体攻击，从而允许存活，目前还知之甚少。*我们的研究小组之前已经制定了一项允许对内皮细胞激活补体的方案。在这个模型中，内皮细胞失去了迁移能力，并耗尽了能量储存(主要是线粒体，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。我们在此建议确定补体攻击期间内皮细胞参与的生存机制，以及确定这些细胞发生的代谢/能量变化，最终允许它们*逃避补体攻击并存活。因此，我们的目标也是确定这些防御机制的“引爆点”，即可能最终使细胞机制不再承受补体攻击的因素，并致力于清除这些受损的细胞，否则将损害生物体。*我们预计会找到各种方法，在补体攻击下，内皮细胞试图保持平衡和功能的细胞内状态，包括抑制细胞用来杀死高度受损的细胞的机制，这更多地依赖于替代能源(除了线粒体)，并试图从它们的*表面移除毛孔。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的活动，那时我们预计会看到*细胞比这些机制活跃时更快地死亡。*由于补体系统在全身普遍存在，我们预计这里提出的研究*项目产生的结果将有可能对人体几乎所有组织/器官系统的细胞/组织生存机制产生基本的新见解，而不仅仅是内皮细胞。

***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.*********