Defining the mechanism of galectin-3

Active TGF is the major pro-fibrotic mediator promoting a variety of fibrotic conditions including Idiopathic Pulmonary fibrosis (IPF). IPF is a progressively fatal lung disease with a median survival post diagnosis of approximately 3 years without a curative therapy. Galectin-3 is a galactoside binding lectin found in the fibroblastic foci in lungs of IPF patients and a galectin inhibitor, TD139 reduced lung collagen in a murine model of lung fibrosis highlighting the potential of targeting galectin-3 in IPF.
Primary lung fibroblasts from IPF patients, and controls, will be stimulated with recombinant galectin-3 and fibrogenic molecules in the presence/absence of integrin and galectin inhibitors. The effects on TGF activation and markers of fibrosis will be compared. The effect of galectin-3 on expression, localization and clustering of 1 and 5 integrin on fibroblast cell surfaces will be assessed by immunofluoresence. The effect of galectin-3 on RhoA mediated cytoskeletal rearrangement, a key intermediate step in TGFb activation, will be assessed by GLISA, and live cell imaging. The interaction between galectin-3 and integrins and latent TGF we will be assessed by binding assays.
This proposed study will equip the student with a range of laboratory techniques and experimental skills. They will gain specialized knowledge in a rapidly developing field and become expert in oral and written presentation. New knowledge will be generated, and disseminated through scientific meetings, patient support groups and charities as well as high impact peer reviewed publications. Successful delivery of this study will facilitate translation of galectin-3 inhibitors into therapies for patients through collaboration with Galecto Biotech.