Jane Sottile, Ph.D.
Associate Professor, Department of Medicine, Aab Cardiovascular Research Institute
1987 | PhD | Arts & Sciences | State University at Albany
1979 | BA | Biology | Marist College
A precise balance between the deposition and degradation of extracellular matrix molecules (ECM), including type I collagen and fibronectin, is required for normal tissue function, and is a key component of normal tissue repair. The studies in my lab are focused on understanding the mechanisms that control extracellular matrix remodeling. Our data show that the extracellular matrix protein, fibronectin, plays a key role in controlling the deposition and stability of extracellular matrix proteins, including type I collagen. Our data also demonstrate that fibronectin-dependent extracellular matrix remodeling regulates adhesion-dependent cell growth, cell contractility, and cell migration. We are currently studying the mechanisms by which fibronectin regulates extracellular matrix remodeling, cell growth, and cell migration using in vitro, ex vivo and in vivo approaches. These studies will provide important insights into factors that contribute to the development of fibrosis, and into mechanisms that could prevent the progression of fibrosis. These studies will also provide important insights into the complex interplay between smooth muscle cells and extracellular matrix, which plays a crucial role in the development and progression of vascular disease.
Molecular mechanisms that regulate extracellular matrix remodeling. Strategies to reduce the excess accumulation of ECM during fibrosis have mainly focused on decreasing the synthesis or promoting the extracellular proteolysis of ECM proteins. Our studies focus on examining the role of endocytosis in regulating ECM accumulation. Our studies suggest that a positive feedback mechanism exists in which ongoing fibronectin deposition limits the endocytic removal of fibronectin and type I collagen from the ECM, thus contributing to enhanced ECM accumulation. We are currently examining the role of the matrix modifying enzyme, membrane type I matrix metalloproteinase (MT1-MMP), and the fibronectin endocytic receptor, a5b1 integrin, in regulating the cleavage and/or endocytic removal of extracellular matrix fibronectin and type I collagen.
Regulation of fibrosis by fibronectin. A key event in fibrosis is the excess accumulation of ECM proteins. Our in vitro and in vivo studies show that fibronectin is an important regulator of ECM remodeling. We are using different animal models of fibrosis to examine how the process of fibronectin matrix deposition regulates the inflammatory response and the excess deposition of extracellular matrix proteins during fibrosis.
Regulation of vascular remodeling by fibronectin. Vascular remodeling occurs in a variety of diseases, such as atherosclerosis, hypertension and restenosis. Because extracellular matrix molecules are important regulators of cell growth and migration, changes in extracellular matrix composition and organization during vascular remodeling can contribute to changes in smooth muscle cell behavior. We are using a flow-induced vascular remodeling model in mouse carotid arteries to study how fibronectin inhibitors regulate extracellular matrix remodeling in vivo. We are also using cultured smooth muscle cells to determine how fibronectin regulates smooth muscle cell phenotypic modulation, as well as smooth muscle cell and immune cell migration.
MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin. Shi, F., and Sottile, J. 2011. 2011 J. Cell Sci. 124:4039-50.
Collagen I matrix turnover is regulated by fibronectin polymerization. Shi, F., Harman, J., Fujiwara, K., and Sottile, J. 2010. Am J Physiol Cell Physiol. 298:C1265-75.
Fibronectin is an important regulator of flow-induced vascular remodeling.
Chiang HY, Korshunov VA, Serour A, Shi F, Sottile J., Arterioscler Thromb Vasc Biol. 2009 Jul;29(7):1074-9. Epub 2009 Apr 30.
Caveolin-1-dependent beta1 integrin endocytosis is a critical regulator of fibronectin turnover. Shi F, Sottile J. J Cell Sci. 2008 Jul 15;121(Pt 14):2360-71. Epub 2008 Jun 24.
Fibronectin-dependent collagen I deposition modulates the cell response to fibronectin.
Sottile J, Shi F, Rublyevska I, Chiang HY, Lust J, Chandler J., Am J Physiol Cell Physiol. 2007 Dec;293(6):C1934-46. Epub 2007 Oct 10.