Research

Ferreira, Viviana P., D.V.M., Ph.D.

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Contact: viviana.ferreira@uthct.edu

Education:
D.V.M., 1995, School of Veterinary Medicine and Livestock Sciences, University of Chile, Chile.
Ph.D. in Biomedical Sciences, 2004, School of Medicine, University of Chile, Chile.

Research Interest:
Regulation of the complement system. Mechanisms of cell protection from complement-mediated damage. Functional consequences of interactions between complement regulatory proteins and non-complement related proteins.

Lay Summary:
The complement system is an essential part of the body’s innate defense system against pathogenic microorganisms or cells (i.e tumors). The complement system can kill directly, or mark the target with molecules (C3b, iC3b, C3d) that can be recognized by a more specialized defense system (the acquired immune system) for elimination. It is composed of over 30 serum and cell surface proteins that interact with one another and with other molecules of the immune system to generate important effectors of innate and adaptive immune responses. Although complement activation is essential to the body’s defense system, it also contributes to the origin of many chronic and acute inflammatory diseases, such as acute myocardial infarction and renal disease. In order to protect host cells from damage by complement activation, the complement system uses a complex set of regulator molecules that are either bound to the surface of cells (DAF, CR1, CD59, and MCP), or that are circulating in the blood (factor H, factor I and C4bp). Our research is aimed at understanding the molecular mechanisms by which various complement regulatory proteins combine efforts to protect cells of diverse tissue origin from normal or excessive complement-mediated attack. These studies will contribute to the understanding of how cells protect or fail to protect themselves when under attack by complement, and how this failure to protect can lead to the progression and severity of diseases. Our studies on how complement is regulated on cell surfaces may also contribute to the development of drugs aimed at preventing complement-mediated damage of our own normal cells or promoting complement-mediated lysis of unwanted pathogenic cells, such as those found in cancer.

Research Overview:
The complement system uses a complex set of complement regulatory proteins that are either membrane-bound (DAF, CR1, CD59, and MCP) or in the fluid phase of plasma (factor H, factor I and C4bp). Factor H is a soluble complement regulatory molecule with an essential role in the control of complement activation in plasma and on cell surfaces. The role of factor H as a soluble molecule with the ability to play a major role in the protection of cell surfaces has been frequently overlooked. We have recently shown that factor H is essential for the protection of cell surfaces using normal and paroxysmal nocturnal hemoglobinuric (PNH) human red blood cells as models. Since factor H has been shown to be present in cardiovascular disease lesions and to bind to vascular endothelial cells, which are constantly exposed to circulating complement, we are currently determining the role of factor H in protection of cells of cardiovascular origin, in the presence or absence of the membrane-bound complement regulatory molecules. We are determining the contribution of each regulatory molecule, individually and in combination, to the protection of these cell surfaces from complement-mediated attack. In addition, factor H has been identified as a major binding protein for various molecules that are not part of the complement system (i.e. C reactive protein, DNA), but that have the ability to promote complement activation. These molecules are acute-phase markers of severity in many disease processes, such as inflammatory heart disease and infections, and we are investigating the functional consequences of these interactions on factor H-mediated complement regulation. Finally, factor H polymorphisms and mutations have been linked to human diseases that often lead to severe complement-mediated tissue damage such as atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (ARMD), and membranoproliferative glomerulonephritis (MPGN). Understanding the molecular mechanisms of how factor H contributes to the protection of different cell surfaces from complement-mediated damage, determining its relative contribution to protection compared to the membrane bound complement regulatory proteins, and identifying how mutations in factor H affect its ability to protect will help elucidate its role in the prevention or pathogenesis of these and other diseases where complement-mediated tissue damage plays an important role.

Selected Papers and Abstracts: