Genetic Dissection of the Role of Smarcb1, Lztr1, and Nf2 Inactivation in Schwannomatosis-Related Tumorigenesis and Neuropathic Pain
Abstract
Schwannomatosis is a rare form of neurofibromatosis that has only recently been identified. This genetic disorder affects less than 1 in 40,000 people and causes the development of benign tumors (called schwannomas) that usually grow on spinal and peripheral nerves. These tumors develop when Schwann cells, which form the insulating cover around nerve fibers, grow abnormally. The tumors may cause pain that may be hard to manage. Tumor development appears to be primarily related to a change, or mutation, in certain genes that help regulate cell growth in the nervous system. So far, two of these genes have been identified as mutated in schwannomatosis patients (SMARCB1 and LZTR1). In addition, the NF2 gene is mutated in schwannomatosis tumors. These mutations prevent the genes from making the normal proteins that control cell proliferation, allowing cells to multiply excessively and form tumors. Despite the recent successes of familial studies to uncover the genetic mutations in schwannomatosis, our understanding of the molecular consequences of loss of NF2 and SMARCB1 or LZTR1 that give rise to schwannomas is still in its infancy. Our central hypothesis is based on the observation that, in contrast to neurofibromatosis type 2 (NF-2), schwannomas in schwannomatosis patients are typically distinctly painful. Thus, SMARCB1 or LZTR1 gene inactivation, which is not typically present in NF-2 schwannomas, could be responsible for the pain phenotype that is not associated to schwannomas in NF-2. We will test this hypothesis by: (1) using genetically engineered mouse models to determine the mechanisms of schwannoma development in schwannomatosis and (2) defining the role of Smarcb1 or Lztr1 gene inactivation in pain associated with schwannomatosis (collaboration with Dr. Michael Caterina, Johns Hopkins School of Medicine). This work will provide the research community with novel model systems and databases of gene expression profiles from each model that can be used to design and perform preclinical tests of agents to relieve pain and tumor growth in schwannomatosis. The successful completion of this study will lead to a major leap forward in our understanding of schwannomatosis manifestations and in the availability of tools that can used over the next decade to develop novel, efficacious therapies to control tumorigenesis and treat this pain.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810776
Entities
People
- Marco Giovannini
Organizations
- United States Army
- University of California, Los Angeles