Grant: Operating Grant - PA: INMHA (bridge funding)

Cells possess a number of mechanisms that help to maintain the number of atoms inside them within normal limits. One such mechanism is the sodium/hydrogen (Na/H) exchanger which transports hydrogen (H) atoms out of cells in exchange for sodium (Na) atoms, which enter them. In many cells outside the nervous system, not only do Na/H exchangers play an important role in removing acid (in the form of hydrogen atoms) from inside cells but also they are involved in regulating cell growth and movement. Nerve cells also possess Na/H exchangers. Although it is known that Na/H exchangers help to remove acid from nerve cells, until recently it was not known whether they also play a role in regulating their growth. We have now found that drugs which reduce the activities of Na/H exchangers slow the rate at which a variety of different types of nerve cells grow and send out branches. Conversely, when we increase the number of Na/H exchangers in nerve cells, they grow more quickly and develop more branches. We have also found that netrin, a protein which is required for the proper development of nerve cells and also helps nerve cells to re-grow after injury, does not stimulate nerve cell growth in the absence of Na/H exchangers. We now propose to build on these and other findings to examine in detail how Na/H exchangers are involved in the growth-promoting actions of netrin in nerve cells. The proposed studies will contribute to our understanding of the mechanisms involved in nerve cell development and may have implications outside the brain. For example, netrin promotes the development and spread of some types of tumours and drugs that slow down the activities of Na/H exchangers may prove to be effective chemotherapeutic agents against these types of cancers.