Maile Research Statement
Work
in my laboratory focuses on the regulation of IGF-I receptor signaling.
Our recent studies have demonstrated that the response of cells to IGF-I
is determined not only by the activation state of the IGF-I receptor
itself but also by several other transmembrane proteins, namely the
integrin V?, integrin associated protein (IAP) and SHPS-1. These three
proteins exert their regulatory effect, at least in part, by their
coordinated regulation of the recruitment, distribution and activation
of the tyrosine phosphatase SHP-2. SHP-2 is a critical regulator of IGF-I
signaling since it dephosphorylates the active receptor and therefore
turns of signaling. In addition SHP-2 activity is also required for
signaling in response to IGF-I since overexpression of a catalytically
inactive mutant of SHP-2 inhibits IGF-I signaling. Insulin-like growth factor -I (IGF-I) is a potent stimulator of smooth muscle cell (SMC) migration and proliferation and there is a significant amount of data to suggest it plays a role in the development of atherosclerosis. One aim of the work being undertaken in this laboratory is to understand the molecular mechanisms by which changes in ligand occupancy of V?, integrin associated protein (IAP) and SHPS-1 regulate IGF-I signaling in SMCs. A second aim is to determine how the subcellular
localization
of these proteins is regulated and how this affects their ability to
regulate IGF-I signaling. The results from these studies will increase
our understanding of the molecular pathways that regulate IGF-I
signaling in SMCs and have the potential to define novel therapeutic
targets allowing targeting inhibition of IGF-I signaling without
activation of adverse side effects. One significant aspect in the development of diabetic retinopathy is the increase in vascular cell proliferation leading to neovascularization or angiogenesis. The formation of new blood vessels is a major contributor to the loss of vision associated with diabetic retinopathy. One factor believed to contribute to the increase in endothelial cell proliferation is an increase bioactivity of IGF-I. Directly targeting the IGF-IR is however unlikely to be a feasible target for the inhibition of IGF-I stimulated endothelial cell proliferation. Very little is known however regarding the molecular mechanisms that regulate the response of retinal endothelial cells to IGF-I. Since our studies in SMCs demonstrated that V?, integrin associated protein (IAP) and SHPS-1 are important regulators of IGF-I signaling we are now investigating their role in the regulation of IGF-I signaling in retinal endothelial cells. The results obtained from these studies will contribute to an enhanced understanding of the molecular mechanisms that regulate endothelial cell growth, which is necessary to fully understand the pathology of diabetic retinopathy. It is hoped that these studies will also lay the foundation for further studies in the development of novel therapeutic targets in the treatment of diabetic retinopathy.
