Interferon alpha (IFN-a) is a cytokine which is critically important to the pathogenesis of systemic lupus erythematosus (SLE). Previous work from our group suggests that increased IFN-a activity is a heritable SLE risk factor, however the genetic regulation of this risk factor is largely unknown. We hypothesize that a number genetic risk factors result in dysregulation of the IFN-a pathway, causing increased IFN-a signaling and subsequent risk of SLE. In this proposal, we will examine the functional significance of candidate genes within the IFN-a pathway. We will measure the contribution of genes associated with SLE to in vivo serum IFN-a activity and downstream IFN-a- induced gene expression in SLE patients. We will also validate a number of novel candidate loci which were associated with serum IFN-a activity in a genome-wide study of our local SLE patient cohort as SLE risk loci in a large independent cohort. Novel candidates which are validated will then be characterized functionally within the IFN-a pathway in a similar manner as above, and we expect that a genetic model of IFN-a regulation in SLE patients in vivo will emerge. Short term career goals include the completion and publication of the preliminary studies which we present in the proposal, as well as a program of coursework in statistical genetics. Data will be presented regularly in lab meetings and chalk talks, and I will meet weekly with both of my mentors. Long term career goals include the characterizing the novel candidates described in the proposal, and submission of independent investigator-initiated grants such as the NIH R01 based on preliminary data generated in these projects. Additionally, I will participate in the rich scientific environment at University of Chicago, attending seminars and conferences hosted by the Section of Rheumatology, the Section of Genetic Medicine, and the Committee on Immunology. Support from the K Award mechanism will enable me to aggressively pursue both the scientific and educational aims outlined in this proposal.

Public Health Relevance

We will use a combination of genetic and functional analyses to identify the important genetic elements causing IFN-a pathway dysregulation in vivo in SLE patients. This work has direct clinical relevance, as agents targeting the IFN-a pathway are currently a high priority in SLE drug development. Our findings could allow for more specific and personalized therapies targeting the IFN-a pathway in human SLE, and may suggest preventive strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI083790-06
Application #
8508173
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2013-03-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$122,958
Indirect Cost
$9,108
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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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
Kariuki, S N; Ghodke-Puranik, Y; Dorschner, J M et al. (2015) Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus. Genes Immun 16:15-23
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Ghodke-Puranik, Yogita; Niewold, Timothy B (2013) Genetics of the type I interferon pathway in systemic lupus erythematosus. Int J Clin Rheumtol 8:
Balboni, Imelda; Niewold, Timothy B; Morgan, Gabrielle et al. (2013) Interferon-α induction and detection of anti-ro, anti-la, anti-sm, and anti-rnp autoantibodies by autoantigen microarray analysis in juvenile dermatomyositis. Arthritis Rheum 65:2424-9
Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2013) MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus. PLoS Genet 9:e1003336
Rullo, Ornella J; Woo, Jennifer M P; Parsa, Miriam F et al. (2013) Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus. Arthritis Res Ther 15:R18

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