My immediate goals are to obtain credentials and funding to achieve independence as an investigator. In the long run I envision myself with an academic career combining clinical pediatric rheumatology and translational research in the field of autoimmunity, with a particular focus on pediatric rheumatic diseases, including pediatric systemic lupus erythematosus (pSLE). My career development plan is to acquire expertise in a variety of experimental techniques, biological concepts, statistical methods and administrative responsibilities required of an investigator. I have organized an advisory committee of senior investigators to provide guidance during the Award period and my goals will be accomplished by performing experiments, completing courses in biostatistics, attending conferences, participating in patient care, and mentoring students and fellows in the lab and clinic. While significant progress has been made in the treatment of pSLE, patients continue to suffer significant morbidity and mortality including infertility, secondary malignancy, and other end-organ damage. The overall goal of this project is to identify important biomarkers for SLE. Given our expertise with antigen arrays and the large cohort of pSLE patients we are evaluating, we are poised to make significant progress in this important area of SLE biomarker research. My research plan addresses the following hypotheses: 1. autoantibody profiles in pSLE patients differentiate patients with distinct clinical manifestations, these differences are present at onset or evolve during the first 12 months of disease, and epitope spreading within a patient over time predicts risk for disease severity or progression;2. the upregulation of IFN-l-regulated genes resulting in the well-described """"""""interferon biosignature"""""""" in pSLE correlates with the presence of autoantibodies directed against specific nucleic-acid-containing autoantigens;and 3. histone modifications occurring in pSLE patients serve as unique targets for autoreactivity. In my research plan, I propose to profile autoantibodies and evaluate upregulation of IFN-l-regulated genes in pSLE patients. By correlating the results from all 3 Aims with clinical data, we expect to identify important biomarkers that will allow better diagnosis, prognostication and treatment of pSLE patients in the future.
SLE is the second most common rheumatic disease in pediatric rheumatology and pediatric patients often have more severe disease than adult patients. Current therapies are not always effective, relapse is common, and there are significant associated toxicities. Given the future years that lie ahead of these patients, reliable serum biomarkers are needed to allow more accurate diagnosis, prognostication, and treatment of pSLE patients.
|O'Gorman, W E; Kong, D S; Balboni, I M et al. (2017) Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients. J Autoimmun :|
|Haddon, D James; Diep, Vivian K; Price, Jordan V et al. (2015) Autoantigen microarrays reveal autoantibodies associated with proliferative nephritis and active disease in pediatric systemic lupus erythematosus. Arthritis Res Ther 17:162|
|Price, Jordan V; Haddon, David J; Kemmer, Dodge et al. (2013) Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus. J Clin Invest 123:5135-45|
|Balboni, Imelda; Niewold, Timothy B; Morgan, Gabrielle et al. (2013) Interferon-? 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|
|Thibault, Donna L; Graham, Kareem L; Lee, Lowen Y et al. (2009) Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus. Arthritis Res Ther 11:R112|