Sottile Lab

Research Overview

A precise balance between the deposition and degradation of extracellular matrix molecules, including collagen type I 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 collagen I. Our data also demonstrate that the polymerization of fibronectin into the extracellular matrix regulates adhesion-dependent cell growth, cell contractility and cell migration. Agents that disrupt fibronectin polymerization trigger enhanced fibronectin and collagen I turnover; these agents also induce turnover of fibronectin in tissues. These data indicate that extracellular matrix turnover is regulated by fibronectin polymerization. Hence, agents that regulate fibronectin polymerization are likely to be crucial in controlling cell proliferation, migration, and extracellular matrix remodeling, all of which are key events that occur during vascular remodeling, wound healing, and fibrosis. We are currently studying the mechanisms by which fibronectin polymerization 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 critical role in the development and progression of vascular disease.

Feng Shi, Ph.D., Postdoctoral Fellow

Fibronectin matrix turnover occurs through receptor-mediated endocytosis and is followed by lysosomal degradation. My current project is to identify fibronectin endocytic receptor and the endocytic pathways by which fibronectin is degraded. I am also actively investigating the regulatory signaling events, as well as
extracellular proteases that may be involved in fibronectin matrix turnover. Understanding the mechanisms of fibronectin matrix remodeling can provide insights into the development of fibrosis, and possible therapy for reversal of excess matrix accumulation during fibrosis.

Hou-Yu Chiang, Ph.D., Postdoctoral Fellow

Vascular remodeling occurs during the pathological process of vascular diseases, such as atherosclerosis, hypertension and restenosis. In addition to smooth muscle cell (SMC) proliferation and migration, changes in extracellular matrix (ECM) organization and composition in the vessel wall are involved in the process of vascular remodeling. Because ECM is an important regulator of cell growth and migration, changes in ECM composition and organization during vascular remodeling can contribute to changes in SMC behavior. We and others have shown that deposition of FN into the ECM regulates cell proliferation and migration. In addition, inhibition of FN polymerization decreases the formation of collagen fibrils in vitro. We are interested in determining whether inhibition of FN polymerization reduces SMC hyperplasia and neointimal formation by controlling FN and collagen I deposition in blood vessels. We are using a flow-induced vascular remodeling model in mouse carotid arteries to determine whether inhibition of FN polymerization decreases FN and collagen deposition and reduces intima-media thickening. These results will help us to understand ECM-ECM and ECM-cell interactions and could lead to development of a treatment strategy for pathological vascular diseases in the future.

Jennifer Bradburn, Ph.D., Postdoctoral Fellow

My research is focused on understanding how collagen type I matrix is regulated and more specifically on elucidating the mechanisms by which collagen fibrils are endocytosed as the extracellular matrix is turned over. Much of my research uses labeled proteins that can be tracked and whose fate can be determined. Results from this research will aid in the understanding of how matrix proteins influence cell function such as cell proliferation, survival and migration as well as possibly offer new insight into disease pathologies such as atherosclerotic plaque formation or fibrosis which are both associated with elevated levels of collagen type I matrix.

Andrew Serour, B.S., Technical Associate

Drew manages the daily activities of the lab, and is actively involved in many laboratory projects. He provides technical support to all lab members. He also purifies proteins, performs many histological procedures, including tissue sectioning and staining, performs many different molecular biology techniques, and is responsible for maintaining the mouse colonies. Currently, Drew is producing large quantities of recombinant proteins for in vivo studies to examine the effects of fibronectin and collagen inhibitors on fibrosis development and vascular remodeling.

Advancing our understanding of the basic mechanisms responsible for normal and pathological function of the cardiovascular system.