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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24AI078004-05
Application #
8685875
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2010-09-24
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$147,771
Indirect Cost
$10,946
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2016) Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. Ann Rheum Dis 75:2007-2013
Zhao, Jian; Giles, Brendan M; Taylor, Rhonda L et al. (2016) Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. Ann Rheum Dis 75:242-52
Taylor, Rhonda L; Cruickshank, Mark N; Karimi, Mahdad et al. (2016) Focused transcription from the human CR2/CD21 core promoter is regulated by synergistic activity of TATA and Initiator elements in mature B cells. Cell Mol Immunol 13:119-31
Berens-Norman, Heather M; Boackle, Susan A (2016) Editorial: Subduing Lupus: Can Preclinical Autoimmune Disease Be Arrested? Arthritis Rheumatol 68:2357-60
Lu, Xiaoming; Zoller, Erin E; Weirauch, Matthew T et al. (2015) Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. Am J Hum Genet 96:731-9
Kottyan, Leah C; Zoller, Erin E; Bene, Jessica et al. (2015) The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Genet 24:582-96
Zhao, Jian; Wu, Hui; Langefeld, Carl D et al. (2015) Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus. Clin Immunol 161:157-62
Martins, M; Williams, A H; Comeau, M et al. (2015) Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study. Genes Immun 16:142-50
Vaughn, Samuel E; Foley, Corinne; Lu, Xiaoming et al. (2014) Lupus risk variants in the PXK locus alter B-cell receptor internalization. Front Genet 5:450
Guthridge, Joel M; Lu, Rufei; Sun, Harry et al. (2014) Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. Am J Hum Genet 94:586-98

Showing the most recent 10 out of 35 publications