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and IGF-binding protein structure and function
We are studying the dysregulation of the insulin-like growth factor (IGF) system in cancer. In breast cancer and head and neck squamous cell carcinoma cells, we are examining IGF-1 receptor crosstalk to vascular endothelial growth factor (VEGF) signaling in mediating enhanced tumorigenicity and metastasis.
Using retinal pigment epithelial cells as a model, we are studying the interplay between IGF-1 receptor signaling and hypoxia in the regulation of vascular endothelial growth factor production and the loss of intercellular tight junctions. These studies are designed to better understand the contributions of these factors to the choroidal neovascularization accompanying age-related macular degeneration.
An underlying theme of our research is to develop inhibitors of IGF signaling. Toward this end we are employing a number of complementary strategies to develop IGF antagonists using the IGF-binding proteins (IGFBPs) as lead compounds. The IGFBPs are a class of six homologous secretory proteins, which function to block access of the IGFs to the IGF-1 receptor. For these analyses, we are using IGFBP-2 as a template for studies aimed at defining the binding domain for IGF-1. The IGFBPs interact with a specific binding domain on IGF-1 that is distinct from its receptor binding domain. These studies have profound implications for the development of IGF-1 antagonists by designing small molecular weight analogs, structurally identical to the binding site for use in inhibiting the growth of IGF-dependent tumors. These studies also have important applications toward defining the IGF-1 binding domain on the IGF-1 receptor and the development of IGF-1 receptor antagonists.
Toward this end, we are collaborating with Professor H.S. Atreya in the Biomolecular NMR Laboratory at the Indian Institute of Science, Bangalore, India.