Neurofibromatosis type 1 (NF1) is a common genetic disorder with an incidence of 1 in 3500 live births. The disease occurs as a consequence of mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Patients with NF1 have a range of malignant and nonmalignant manifestations such as cutaneous and plexiform neurofibromas. It has been found that patients with NF1 have a profoundly elevated numbers of degranulating mast cells associated in close proximity with Schwann cells, endothelial cells, and fibroblasts. Using a murine model of NF1 that contains a disruption of the murine NF1 homologue (Nf1), it was established that heterozygous disruption of Nf1 results in a range of gain-in-functions that may promote the genesis and progression of neurofibromas. Furthermore, recent studies using a murine model of neurofibroma formation have demonstrated that heterozygous loss of Nf1 in non-neuronal lineages, including mast cells, is required for tumorigenic progression. Mast cells are a known major cellular source of cytokines and chemokines for other cell lineages within the neurofibroma, and they have been implicated in promoting neoangiogensis, as well as altering the extracellular matrix. Despite these theoretical functions, the precise growth factors that are generated as well as the biochemical and molecular mechanisms underlying this gain in function are unknown. Studies in this application propose to dissect these processes.
Studies in Aim 1 of this application will elucidate the mechanisms underlying this gain in function that could lead to the identification of key molecular targets that have a role in treating this common disease manifestation. While many aspects of the human disease are similar to the murine model, there are known species-specific differences in mast cell biology of the human and murine lineages. In Aim 2, I propose to evaluate whether mast cells from NF1 patients have similar functions and whether the cytokine secretion profile changes in human NF1 patients are comparable to the murine model. Further, I will determine whether the biochemical pathways leading to the pathological gain in activity is via the same or a distinctive biochemical pathway to those identified in the murine model.
Collectively, these studies will quantitatively identify the cytokines and other potential substances that would have the biological activity to promote tumor progression and will test potential biochemical pathways that result in a gain in function in these processes in both murine models and primary mast cells cultured from peripheral blood cells of NF1 patients. The goal of these studies is to provide insights into the identification of rational molecular targets for the treatment of neurofibromas.