Grant: Project Grant

Many essential 'housekeeping' functions in the body require acid to be pumped across the membranes of cells and tissues. Acid is pumped into lysosomes, cellular recycling bins that break down old cell components into reusable building blocks, and it is pumped into urine to rid the body of the excess produced during physical activity. Bone repair requires that specialized cells (osteoclasts) secrete acid to dissolve the bone surface prior to its being replaced by new bone. In all these cases, variants of one ubiquitous acid pump, known as V-ATPase, perform the job. Genetic mutations that impair V-ATPase activity are known to cause diseases, such as cutis laxa (wrinkly skin disease), renal tubular acidosis (too much acid in the body), and osteopetrosis (heavy, brittle bones). In contrast, abnormal increases in V-ATPase activity can also lead to diseases, such as osteoporosis (thin, fragile bones) and inflammatory arthritis (eroded joints). In tumours, V-ATPases can acidify and degrade the surrounding tissue, helping cancer cells to detach and spread to other parts of the body. Our goal is to investigate aspects of V-ATPase structure and function that are still poorly understood: the structures and organization of its protein constituents, the variations that cause it to be sent to different locations within cells of the body, factors that control its activity to match its location, and how genetic mutations in V-ATPase genes cause disease. Understanding these factors will reveal new strategies to manipulate the V-ATPase acid pump activity in a manner that is required to alleviate disease. These strategies will enable specific targeting of bone cell or cancer cell V-ATPases without affecting the acid pumps that are engaged in vital housekeeping functions. Specific targeting is a crucial requirement for developing new drugs for the prevention of bone loss in osteoporosis and inflammatory arthritis, or the spread of cancer, without causing serious side effects.