Grant Details
Project Lead | Rosalind A. Segal M.D., Ph.D. |
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Amount | $450,000 |
Year Awarded | |
Duration | 3 years |
DOI | https://doi.org/10.37717/20002065 |
Summary |
Generating the correct number of nerve cells is a difficult and critical process. If too many nerve cells are made, brain tumors, the most common solid tumors in childhood, can develop. We focus on the cerebellum, a part of the brain that controls balance and coordination, and that is a major site of tumors. One cerebellum tumor, medulloblastoma, arises from uncontrolled growth of granule cells. Medulloblastomas develop frequently in people who are born with a genetic disorder (Gorlin's syndrome) in which the sonic hedgehog growth factor becomes overactive. This growth factor can make normal cells divide. Work from insects suggests that sonic hedgehog needs other proteins, such as EXT proteins, in order to work properly. We found that several EXT genes are expressed in developing neurons in the cerebellum. In particular, one EXT is expressed in normal cerebellar cells, and is partially turned off in medulloblastomas. We propose to analyze when and where all these genes are expressed during normal cerebellar development, and whether expression changes in tumors. EXT genes allow cells to make proteoglycan molecules that surround the cells. We have found that when we alter proteoglycans, sonic hedgehog can no longer make granule cells divide. We propose to find out how proteoglycan molecules work with sonic hedgehog to make cells divide. These studies will help us understand how the sonic hedgehog protein works to make the right number of nerve cells, without forming tumors. |