Analysis of Lupus Susceptibility Genes for Treatment and Prevention of Disease

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DESCRIPTION (provided by applicant): This career development award will allow the candidate to expand her research program directed towards understanding the pathogenesis of human systemic lupus erythematosus (SLE), to build an institutional program in patient-oriented research focused on lupus, and to foster the development of clinical researchers interested in the study of lupus. The candidate has demonstrated that complement receptor 2 (CR2/CD21) is a strong candidate gene for lupus susceptibility in the NZM2410 mouse model of lupus as well as in human disease. Her long-term goals are to dissect the functional relevance of lupus susceptibility genes in the pathogenesis of lupus in order to develop more effective therapies for established disease, to identify strategies for intervention prior to the development of disease, and to characterize biomarkers for disease activity to assist in patient management. She has funding for two patient-oriented studies. One project aims to identify functional single-nucleotide polymorphisms (SNPs) and SNP haplotypes in the CR2 gene that are associated with human lupus and characterize the mechanism by which these gene variants influence lupus susceptibility. The second project addresses whether B cell levels of CR2 are a biomarker for lupus disease activity. A third project developed for this grant mechanism will address whether complement-related genes in linkage with CR2 contribute to the association of CR2 SNPs with SLE and whether CR2 risk alleles are associated with the development of preclinical autoimmunity. These projects offer an excellent experience in patient-oriented research to mentees, including junior faculty, fellows, residents, and medical and MSTP students. In addition, the candidate will build an institutional patient-oriented research program in lupus encompassing translational, outcomes, and epidemiological research as well as clinical trials to facilitate clinical research in lupus and offer additional options for trainees. In the short term, this career development award will allow the candidate in develop this research program, enhance her skills in patient-oriented research, and mentor trainees interested in careers in clinical research. In the long term, it will advance our understanding of the pathogenesis of lupus, lead to the identification of new therapies and preventive measures for this disease, and increase the number of well-trained investigators in patient-oriented research. Project Narrative: This career development award will support the development of an outstanding program in patient-oriented research in lupus at the University of Colorado Denver to facilitate the applicant's research as well as that of her trainees in patient-oriented research. It will result in advances in the treatment of patients with lupus through high quality patient-oriented research performed by well-trained clinical investigators.