Identifying Neurofibromin-Specific Regulatory Nodes for Therapeutic Targeting in NF1
Abstract
Neurofibromatosis type I (NF1) is a genetic disorder affecting 1 in 3500 people worldwide. It is the most common inherited disorder caused by a single gene, and, other than surgical resection of tumors, there is currently no means of treatment. Patients with NF1 suffer from such problems as multiple neurofibromas, optic nerve gliomas, multiple Lisch nodules, osseous lesions, neurobehavioral disorders, which are all caused by cells misbehaving in a way that causes them to proliferate, migrate, or survive when they otherwise should not. NF1 is caused by mutations in the NF1 gene, causing the Neurofibromin protein to stop functioning. Neurofibromin is an inhibitor of the Ras proteins. Ras proteins drive cells in the body to survive, proliferate, and migrate. Thus, when an inhibitor, such as Neurofibromin, is lost, cells hyperproliferate, over-migrate, and/or survive when they otherwise should die. Interestingly, loss of Neurofibromin function only seems to affect specific cell types. This project, "Identifying Neurofibromin-Specific Regulatory Nodes for Therapeutic Targeting in NF1," aims to determine the molecular basis behind why some cells types are affected by Neurofibromin loss and others are not. Many signals in the body, which are often cell type-specific, activate Ras, and some of these signals rely on Neurofibromin to subsequently turn off Ras. This study aims to determine which signals are most dependent on Ras and are thus most sensitive to loss of Neurofibromin (as is the case in NF1 patients). In this manner, we can determine which signals should be targeted with drugs in patients. Having a molecular understanding of which signals or combinations of signals are pertinent to target in NF1 will be invaluable to driving forward the treatment of patients with NF1. Further, we plan to identify unknown regulator proteins of Neurofibromin. This will significantly enhance our understanding of how Neurofibromin is regulated in the cell. Gaining a deep molecular understanding of Neurofibromin signaling is essential for a rational approach to discovering drugs for treating NF1. Using drugs that target specific molecules in diseased cells requires an extensive knowledge of the molecular basis of the disease. The research proposed here will identify molecular vulnerabilities in the cells that have lost Neurofibromin and will ultimately help NF1 patients with the development and use of new drugs for treating various aspects of NF1 disease. The results from this study are essential to properly guide the clinical development of drugs and use of current drugs for NF1 patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510425
Entities
People
- Frank McCormick
Organizations
- United States Army
- University of California, San Francisco