Analysis of Lupus Susceptibility Genes for Treatment and Prevention of Disease

描述（由申请人提供）：该职业发展奖将允许候选人扩展其研究计划，以了解人类系统性红斑狼疮（SLE）的发病机制，建立以患者为导向的狼疮研究机构计划，并促进对狼疮研究感兴趣的临床研究人员的发展。候选人已经证明补体受体2 （CR2/CD21）在狼疮小鼠模型和人类疾病中是狼疮易感性的强候选基因。她的长期目标是剖析狼疮易感基因在狼疮发病机制中的功能相关性，以便为已建立的疾病开发更有效的治疗方法，在疾病发展之前确定干预策略，并表征疾病活动的生物标志物，以协助患者管理。她有两项以病人为导向的研究的资金。一个项目旨在鉴定与人类狼疮相关的CR2基因的功能单核苷酸多态性（SNP）和SNP单倍型，并表征这些基因变异影响狼疮易感性的机制。第二个项目研究B细胞CR2水平是否是狼疮疾病活动性的生物标志物。为该资助机制开发的第三个项目将研究与CR2相关的补体相关基因是否导致CR2 snp与SLE的关联，以及CR2风险等位基因是否与临床前自身免疫的发展相关。这些项目为学员（包括初级教师、研究员、住院医师、医学和MSTP学生）提供了以患者为导向的研究的绝佳体验。此外，候选人将建立一个以患者为导向的狼疮研究项目，包括转化、结果、流行病学研究以及临床试验，以促进狼疮的临床研究，并为学员提供额外的选择。在短期内，该职业发展奖项将允许候选人发展该研究项目，提高她在以患者为导向的研究方面的技能，并指导对临床研究感兴趣的学员。从长远来看，它将促进我们对狼疮发病机制的理解，导致这种疾病的新疗法和预防措施的确定，并增加训练有素的以患者为导向的研究人员的数量。

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.