This proposal describes a 5 year training program for the development of a basic science academic career in rheumatology. The principal investigator received a Ph.D. at the University of Chicago in biochemistry and has completed postdoctoral training in oncology and rheumatology at UCLA. He will further his translational studies in the mechanisms behind accelerated atherosclerosis in systemic lupus erythematosus (SLE) with an interdepartmental, multifaceted approach utilizing genomic, proteomic, and mouse studies. Dr. Bevra Hahn will be the principal investigator's primary mentor for this project. She is the chief of rheumatology at UCLA and is an internationally recognized SLE expert who has mentored numerous scientists and clinicians currently running their own research programs. In addition, the principal investigator will have a diverse mentoring committee, including Dr. Mohanad Navab, Professor of Medicine and an atherosclerosis/monocyte expert;Dr. Joseph Loo, Professor of Chemistry and Biochemistry and the director of UCLA's proteomics core;Dr. Antonio La Cava, Adjunct Associate Professor of Medicine and an expert in murine SLE models;Dr. Steve Horvath, Professor of Human Genetics and Biostatistics, who is a microarray statistical expert and a pioneer in gene network analysis;and Dr. Jennifer Grossman, Associate Professor of Medicine and an expert in clinical SLE. Accelerated atherosclerosis is a major co-morbid condition of SLE that is poorly understood. This proposal focuses on examining primary human monocytes, the primary immune cell mediator of atherosclerosis, at the genomic and proteomic levels to understand the molecular changes that occur as atherosclerosis is initiated in SLE patients. Previous work in the lab demonstrated that a dysfunctional form of high-density lipoprotein (piHDL) is correlated with the initiation of carotid artery plaque, and the principal investigator will use piHDL as a biomarker to stratify SLE patient groups for whole-genome transcriptional, as well as proteomic, studies. Altered genes identified in these experiments that correlate to atherosclerosis initiation and progression will drive in vitro targeted therapeutic studies that will ultimately translate into in vivo preclinical drug intervention studies in a mouse model of SLE and atherosclerosis. This will be the first detailed genomic and proteomic study of monocytes in SLE and will shed considerable light on why SLE patients, and possibly many autoimmune patients, suffer from accelerated atherosclerosis. The Rheumatology division, and the Department of Medicine at UCLA as a whole, provides an ideal setting for training basic scientists in translational medicine by offering a wide range of excellent mentors, facilities, and educational opportunities. UCLA is an ideal place for the principal investigator to transition into an independent academic career.
Accelerated atherosclerosis is a major cause of morbidity and mortality in systemic lupus erythematosus patients. We anticipate that this 5 year study will provide significant insight into the pathogenesis of atherosclerosis in SLE, as well as identify molecules that can be targeted as novel therapeutic options in SLE patients at risk of developing cardiovascular disease. These studies, therefore, have the potential to improve patient care and health in SLE and other autoimmune diseases.
|McMahon, Maureen; Skaggs, Brian J; Grossman, Jennifer M et al. (2014) A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheumatol 66:130-9|
|Skaggs, Brian J; Hahn, Bevra H; McMahon, Maureen (2012) Accelerated atherosclerosis in patients with SLE--mechanisms and management. Nat Rev Rheumatol 8:214-23|
|Leder, Kevin; Foo, Jasmine; Skaggs, Brian et al. (2011) Fitness conferred by BCR-ABL kinase domain mutations determines the risk of pre-existing resistance in chronic myeloid leukemia. PLoS One 6:e27682|
|Skaggs, B J; Lourenco, E V; Hahn, B H (2011) Oral administration of different forms of a tolerogenic peptide to define the preparations and doses that delay anti-DNA antibody production and nephritis and prolong survival in SLE-prone mice. Lupus 20:912-20|
|McMahon, Maureen; Skaggs, Brian J; Sahakian, Lori et al. (2011) High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids. Ann Rheum Dis 70:1619-24|
|Rubbi, Liudmilla; Titz, BjÃ¶rn; Brown, Lauren et al. (2011) Global phosphoproteomics reveals crosstalk between Bcr-Abl and negative feedback mechanisms controlling Src signaling. Sci Signal 4:ra18|
|McMahon, Maureen; Hahn, Bevra H; Skaggs, Brian J (2011) Systemic lupus erythematosus and cardiovascular disease: prediction and potential for therapeutic intervention. Expert Rev Clin Immunol 7:227-41|
|Graeber, T G; Heath, J R; Skaggs, B J et al. (2010) Maximal entropy inference of oncogenicity from phosphorylation signaling. Proc Natl Acad Sci U S A 107:6112-7|
|Skaggs, Brian J; Hahn, Bevra H; Sahakian, Lori et al. (2010) Dysfunctional, pro-inflammatory HDL directly upregulates monocyte PDGFR*, chemotaxis and TNF* production. Clin Immunol 137:147-56|
|Hahn, B H; Lourencco, E V; McMahon, M et al. (2010) Pro-inflammatory high-density lipoproteins and atherosclerosis are induced in lupus-prone mice by a high-fat diet and leptin. Lupus 19:913-7|