Nowling Research Lab

The overarching goal of the Nowling lab is to pursue research that will lead to improving the lives of patients that suffer from Systemic Lupus Erythematosus (SLE or lupus). SLE is a chronic autoimmune disease characterized by increased production of autoantibodies, formation and deposition of immune complexes in target tissues, inflammation, and tissue damage. The most severe complication of SLE is kidney disease (lupus nephritis), which affects up to two-thirds of lupus patients and is associated with increased morbidity and mortality. The lab pursues two major areas of investigation focused on lupus nephritis. The first is to better understand the mediators and pathways that promote disease, which are not completely known or understood. The Nowling lab in collaboration with several other labs was the first to demonstrate that glycosphingolipid (GSL) metabolism is altered in lupus nephritis. Specifically, we demonstrated that the GSLs lactosylceramide (LacCer) and glucosylceramide (GlcCer) were significantly elevated in the kidney and urine of lupus prone mice and lupus patients with nephritis, suggesting GSL metabolism plays a role in disease progression. Currently, the lab utilizes cultures of primary human renal cells and glomeruli (as a “3D” culture system) to elucidate the molecular and cellular mechanisms by which GSLs modulate renal cell function following inflammatory insult. In particular, we are focused on the role GSL metabolism plays in cell-cell communication and pathological responses that contribute to disease progression and tissue damage in the kidney. Additionally, we are interested in sex differences in GSL metabolism, specifically how GSLs modulate calcium signaling and cellular/endoplasmic reticulum (ER) stress in the pathological responses of renal cells.

The second area of investigation involves the identification of biomarkers. Our published studies demonstrated that the levels of GSLs in the urine were significantly elevated prior to treatment in lupus nephritis patients who did not respond to standard of care therapy compared to patients who had a complete response. These results suggested GSLs may serve as non-invasive biomarkers to predict therapeutic response. In addition to GSLs, we more recently demonstrated significant changes in patterns of N-linked glycosylated peptides (N-glycans) in the urine, serum, and renal biopsies of lupus nephritis patients compared to healthy individuals. We are currently expanding our biomarker analyses on a larger number of patients to confirm our initial observations, as well as to investigate changes in these molecules over time with respect to clinical disease measures. The ultimate goal of these studies is to identify a panel of biomarkers that could be used to screen lupus patients to predict which patients are unlikely to respond to standard therapies and/or which patients are likely to develop nephritis.

The lab also utilizes well-established pre-clinical mouse models of lupus to better understand and translate observations in cell cultures to disease pathology. The Nowling lab is highly collaborative with ongoing robust studies with colleagues in the areas of renal physiology, renal endothelial function, imaging mass spectrometry, and biostatistics. Importantly, the Nowling lab strongly values varied viewpoints, ideas, and experiences, which serves to ensure robust and innovative research in a supportive environment. Past and current funding includes grants from the Department of Defense, Lupus Research Alliance, the Veterans Administration, and the National Institutes of Health.

Publications

PubMed Collection