Basement membranes are ubiquitous and conserved sheets of extracellular matrix that separate tissue types and compartments. The thickness and stiffness of basement membranes varies in different tissues, even though they all share a common set of core components, and the origin and maintenance of these differences is not understood. Despite extensive biochemical knowledge of their in vitro assembly, they are often considered to be static after they have formed, and so very little is known about how basement membranes are maintained in health or how they are repaired after damage. Recent data from my laboratory indicates that assembled basement membranes in adult tissues are surprisingly dynamic, requiring continuing crosslinking and proteolysis for their proper function even in the absence of external damage. This proposal will investigate mechanisms of basement membrane homeostasis and repair. First, we will measure their assembly and disassembly rates in undamaged tissue, and then determine how crosslinking and proteolysis affect those rates. Second, we will determine how homeostasis is similar to and different from the process of repair, investigating turnover rates and sources of basement membrane components; and we will screen to identify new genes important to basement-membrane maintenance and repair. Finally, we will test an exciting and novel model that may explain how some basement membranes have different properties than others, a model centered on the activity of the collagen chaperone SPARC. All these aims will utilize Drosophila melanogaster, which has a compact genome and excellent genetic tools. The discoveries emerging from this study will be important to cell biology generally, to tissue repair specifically, and they will have clinical relevance to diseases of basement membrane and to tumor metastasis, as basement membranes are important obstacles to cancer cell migration, and understanding their dynamics will shape models of tumor metastasis.
Basement membranes are important extracellular components of nearly all animal tissues, providing support and separating compartments. Although they are frequently thought of as static and unchanging, our recent data suggests that basement membranes are surprisingly dynamic. We will analyze the processes of basement membrane maintenance and repair, and our findings will be relevant to basement membrane diseases and to tumor metastasis, as dynamic basement membranes may be breached by tumor cells in unexpected ways.
