SUMMARY
Progression of chronic kidney disease(s), cardiovascular disease(s) observed in patients with chronic kidney disease and renal cell cancers are attributable in part, to the dysregulation of important cellular functions including cellular proliferation, extracellular matrix production, and cell migration. Efforts currently underway in our laboratory are focused on understanding fundamental pathways employed by hormonal and growth factor signaling pathways in the pathophysiology of chronic kidney disease progression, associated cardiovascular disease in the setting of kidney disease, and renal cell cancer. With our collaborators, the laboratory investigates cellular signaling cascades initiated by plasma membrane receptors and intracellular receptors identified in renal cells, vascular cells, and cells obtained from renal malignancies. Substantial efforts are underway to elucidate how the signals for abnormal growth are elicited, subsequently transmitted to nucleus and ultimately to the downstream effectors that alter cell phenotype and function. The laboratory has developed a special interest in cellular signaling pathways initiated and regulated by oxidative stress and the generation of reactive oxygen species. Upstream signaling events (e.g.; those activated by vasoactive ligands like serotonin, angiotensin II, and non-esterified fatty acids (NEFAs, among others) regulating various downstream mitogenic cascades and/or signaling cross-talk can be identified by using a variety of approaches including enzymatic and chemical inhibitors, dominant negative/gain of function signaling constructs, antisense oligonucleotides, along with additional molecular and biochemical approaches currently available in our laboratory. Some of the state of the art methodologies currently in use in the laboratory include the production and maintenance of renal cell culture(s), cell transfection techniques, Western blotting, fluorescence and bioluminescent resonance energy transfer studies (FRET and BRET) to assess protein-protein interactions, and additional assays for evaluating cellular proliferation, cell injury, cell migration, matrix production, oxidant production, and transcriptional regulation. Emphasis is placed on identifying the links between vasoactive hormonal agonists, and downstream signaling pathways mediated via regulatory protein kinases and modulation of the phosphorylation state of plasma membrane proteins, intracellular proteins, and specific transcription factors, among others.
The studies are designed to define new pathways that can be targeted therapeutically to slow the progression of chronic kidney disease, associated cardiovascular co-morbidities, and abrogate the growth of renal malignamcies.