Grant: Project Grant

CTGF is a cysteine-rich matricellular protein involved in the control of biological processes, such as cell proliferation, differentiation, adhesion and angiogenesis, as well as multiple pathologies, such as tumor development and tissue fibrosis. Therefore, CTGF and its interaction network defines a powerful mechanism for both therapeutic strategies in fibrosis and cancer. It has been demonstrated that inhibition of human melanoma cells migration targeting metastatic melanoma or modulation of pancreatic ductal adenocarcinoma neoplastic cell responses are promising therapeutic CTGF-based strategies in clinical trials. We aim to perform an integrated structural biology approach, combining protein X-ray crystallography in conjunction with SAXS, AUC/DLS/SEC-MALS and in-depth biochemical and functional assays. When combined, these tools create a detailed molecular understanding of how CTGF acts on its binding partners, and how the activated receptors together work to influence the cell physiology. This research proposal aims to define the molecular basis of CTGF-TGF beta and CTGF-IGF complex interactions and to unravel the structural basis for relevant signaling pathways. In these studies we will seek to develop new therapeutic targets with the overall goal to interrupt CTGF-mediated receptor complexes and thereby causing apoptosis in tumor cells.