Many of the immunological effects attributed to the third component of complement (C3) are mediated or regulated by cell membrane receptors and regulatory proteins, including Complement Receptor l and 2 (CRl,CR2), membrane cofactor protein (MCP), and decay-accelerating factor (DAF). I have been interested in the analysis of these proteins in normal and autoimmune states, and in the creation of animal models to study these molecules. After my clinical training, I have spent three years in Dr. V. Michael Holers' laboratory characterizing the mouse homologues of CRl and CR2, and the mouse functional counterpart of MCP and DAF, the Crry/p65 protein. I have acquired extensive experience in this area and also in different techniques of molecular biology and Immunology. I cloned several mouse CRl, CR2 and Crry transcripts, and a portion of the mouse CRI/CR2 gene. In addition, I established the relation of our genetic homologues with the immunochemically characterized proteins. I evaluated the function of these proteins and identified Crry/p65 as a functional homologue of MCP and DAF. I now propose to create A mouse deficient in these mouse complement receptors and regulatory proteins using gene targeting techniques. The deficient mice will be analyzed for abnormal lymphoid development in addition to complement mediated tissue damage and dysregulation of T-dependent and T-independent antibody responses. My supervisor will be Dr. David Chaplin. He has a background in the genetics of the complement system and substantial technical expertise in gene targeting. Furthermore, complement is a main research area within our Rheumatology division. Finally, Washington University has a large number of investigators who have substantial experience in many aspects of the immune response, providing an excellent environment to pursue this type of research.
| Molina, H; Holers, V M; Li, B et al. (1996) Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc Natl Acad Sci U S A 93:3357-61 |
| Molina, H; Kinoshita, T; Webster, C B et al. (1994) Analysis of C3b/C3d binding sites and factor I cofactor regions within mouse complement receptors 1 and 2. J Immunol 153:789-95 |
