This is an application for an integrative research effort to understand and define the mechanisms by which complement exerts its biological functions in models of ovarian cancer and in processes of tissue regeneration and cell injury. The molecular and cellular basis of complement activity in these settings is not yet fully understood. The proposed Program will clarify this by bringing together investigators with profound expertise in different fields of complement biology, who share the same appreciation for the complexity of the system and are committed to addressing and elucidating the basic mechanisms that underlie these complement-modulated processes. Each laboratory involved has developed well-defined model systems that will allow the dissection of the critical components and mechanisms by which the complement system participates in cell survival or disease pathogenesis. The laboratory of Dr. Lambris will investigate the role of complement in liver regeneration. Well-established models of partial hepatectomy and toxic liver injury using various complement system knockout mice will clarify this. The laboratory of Dr. Coukos will investigate the role of the complement system in ovarian cancer. The role of the complement components and receptors will be analyzed using a transgenic ovarian cancer model. To modulate complement mediated cell proliferation during liver regeneration and cancer development or tissue damage associated with toxic liver injury, the laboratory of Dr. Lambris will further optimize existing therapeutics and design novel ones. His laboratory will develop and characterize specific inhibitors of complement activation and function, and compare their efficacy in the experimental in vivo models. The combined effort of the laboratories involved will elucidate the convergences of mechanisms by which complement exerts its functions in tumor initiation and growth versus tissue regeneration in order to identify suitable therapeutic targets in both settings. The principal investigators involved with these projects have a long history of scientific interaction that they wish to maintain and expand through the successful funding of this application. PROJECT 1: COMPLEMENT AND CYTOKINE NETWORK IN LIVER REGENERATION, Lambris. J PROJECT 1 DESCRIPTION (provided by applicant): 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. ? In 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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