Visualising the early secretory pathway in situ

All eukaryotic cells are organised in membrane-bound compartments which perform essential and distinct functions dependent on their protein, lipid and small molecule composition. Several highly regulated transport pathways ensure that the right components are transported to the right organelle at the right time. Complex multicellular organisms use membrane transport to secrete proteins to the extracellular environment, including hormones, immunoglobulins, and components of the extra-cellular matrix (ECM). Many ECM components, including collagen (the most abundant secreted protein in animals) are very large proteins, which pose a challenge for intracellular membrane transport systems. Dysregulation of collagen secretion is linked to a number of diseases, including genetic defects in cartilage formation that arise from mutations in membrane-transport components, as well as organ fibrosis that happens upon excessive collagen deposition during wound healing. Fibrosis can develop upon injuries caused by a number of common conditions such as diabetes, hypertension, cardiomyopathies, hepatitis, idiopathic pulmonary disease, cancer, and more. This can in turn lead to failure of vital organs as parenchymal tissue is disrupted by excessive ECM. Consequently, severe fibrosis is estimated to account for up to 45% of all deaths in the developed world. Despite its fundamental importance in health and disease, we still do not fully understand how large ECM components are transported between membrane compartments and secreted to the extracellular environment. In this grant, we aim to illuminate the membrane transport pathway that mediate collegen secretion using advanced imaging methodologies.