Areas of Research: Basic mechanisms of vascular remodeling and obstruction, including relevant inflammatory, metabolic, and signaling pathways, with evaluation via mouse models of vascular injury, graft vascular disease, and atherosclerosis.
Vascular disease, the greatest single cause of morbidity and mortality in developed societies, results from interactions between circulating inflammatory cells, the endothelium that lines the vasculature, underlying vascular smooth muscle cells (VSMCs) that comprise most of the arterial wall, and stem/progenitor cells found in the surrounding adventitia. The underlying pathogenesis is complex: factors that impinge on these cell types include reactivated developmental pathways, innate and acquired immune responses, and changes in cell function that result from physical stresses, perturbed blood flow, and biochemical stimuli. Our general approach is to characterize these responses at the molecular level, in cultured cells, and in mouse models that reflect specific types of vascular injury, including atherosclerosis, mechanical trauma, and transplant-associated arteriosclerosis.
Fat proteins are important regulators of cell growth and planar cell polarity. We have linked the atypical cadherin adhesion molecule Fat1 to significant effects on mammalian vascular remodeling. Our studies in VSMCs show that Fat1 interacts with beta-catenin to limit canonical Wnt signaling, a core developmental pathway that regulates many aspects of metazoan embryogenesis, and with Atrophin proteins to control VSMC directional migration. Recent findings suggest that Fat1 is an important regulator of VSMC growth and differentiation in injured vessels, and ongoing studies aim to understand the intracellular and extracellular signals that emanate from Fat1 in cis- and trans-signaling modes. Direct studies of beta-catenin indicate that its expression in VSMCs is required for vascular formation in development and important in adult arterial injury response. Efforts to understand beta-catenin’s essential function in these settings are underway.
Diabetes and obesity are important risk factors for cardiovascular disease. We are investigating how allograft inflammatory factor-1 (Aif-1), a 17 kD Ca2+-binding protein contributes to these conditions. Specific Aif-1 isoform-dependent functions that underlie effects on macrophage migration, phagocytosis, survival, and inflammatory signaling are subjects of ongoing studies. Finally, in collaboration with Richard Stanley, we have characterized a role for colony stimulating factor-1 (CSF-1), the main regulator of macrophage survival, proliferation, and differentiation, in control of transplant-associated arteriosclerosis, the major barrier to long-term success of organ transplants. Surprisingly, this effect appears to involve VSMC-associated CSF-1 in an autocrine/juxtacrine mechanism that is largely independent of macrophages.
Ongoing work in these areas involves defining the molecular bases for these observations. By identifying such novel mechanisms, we hope to find new targets for therapeutic intervention to improve vascular disease prevention and treatment.
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