Complement activation causes energy and metabolism changes in endothelial cells.

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