The unusual regenerative properties of the liver have evolved as an efficient adaptation that allows this organ to cope with many hazardous conditions, including alcoholism, drug overdose, and viral hepatitis. Recent studies in our laboratory have demonstrated the involvement of complement in the priming phase of liver regeneration. The regenerative response is impaired after partial hepatectomy (PHx) and carbon tetrachloride (CCI4) injury in several mouse strains deficient in complement components. Impairment of regeneration has been demonstrated by a decreased and delayed replication rate of liver cells. Moreover, complement deficiencies have been associated with significant injury to the liver parenchyma after PHx. Our recent data indicate that complement deficiency alters the cytokine milieu after PHx, including cytokines essential for liver cell proliferation and survival. Therefore, we hypothesize that complement proteins are involved in the regulation of two cellular processes crucial for successful regeneration: proliferation of liver cells and hepatoprotection. The current research proposal aspires to elucidate the role of complement components in cell proliferation and survival using the PHx model, and to determine the effect of therapeutic interventions involving the complement system on tissue injury induced by CCI4. The studies in Aim 1 are designed to define the role of individual complement components in cell proliferation and hepatoprotection after PHx. This goal will be achieved by disrupting complement signaling pathways after PHx using mice deficient in various complement components, then monitoring liver cell proliferation and injury. The studies in Aim 2 will dissect the mechanisms by which complement components influence liver cell proliferation and survival after PHx. The serum levels of cytokines known to be essential for liver cell proliferation and survival, together with their downstream targets in the liver, will be analyzed in mice deficient in complement proteins, tin addition, the role of anaphylatoxins in liver regeneration-associated angiogenesis will be investigated.** Finally, the research described in Aim 3 is designed to ascertain whether therapeutic interventions involving the complement system will decrease the magnitude of tissue injury resulting from CCI4-mediated toxicity. The proposed studies should lead to a better understanding of the relationship between regulatory molecules of inflammation and cell proliferation and death, two cellular processes essential for physiology and pathology.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Mastellos, Dimitrios C; Reis, Edimara S; Yancopoulou, Despina et al. (2018) Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria. Semin Hematol 55:167-175
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Chen, Lan-Sun; Kourtzelis, Ioannis; Singh, Rashim Pal et al. (2018) Endothelial Cell-Specific Overexpression of Del-1 Drives Expansion of Haematopoietic Progenitor Cells in the Bone Marrow. Thromb Haemost :
Lamont, Richard J; Koo, Hyun; Hajishengallis, George (2018) The oral microbiota: dynamic communities and host interactions. Nat Rev Microbiol 16:745-759
Bostanci, Nagihan; Bao, Kai; Li, Xiaofei et al. (2018) Gingival Exudatome Dynamics Implicate Inhibition of the Alternative Complement Pathway in the Protective Action of the C3 Inhibitor Cp40 in Nonhuman Primate Periodontitis. J Proteome Res 17:3153-3175
Ricklin, Daniel; Mastellos, Dimitrios C; Reis, Edimara S et al. (2018) The renaissance of complement therapeutics. Nat Rev Nephrol 14:26-47

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