Neurofibromatosis type 1 (NF1) is a genetic disorder that affects around 1:3000 live births. While the disease has nearly 100% penetrance in patients, NF1 has a diverse spectrum of manifestations. Hallmark traits of the disease include caf-au-lait macules, cutaneous neurofibromas (cNF), plexiform neurofibromas (pNF) and malignant peripheral nerve sheath tumors (MPNST), among other symptoms. In NF1 patients, cNFs usually arise at puberty and beyond, can range widely in size and number, and can cause itching, pain, superficial infections as well as psychosocial and cosmetic burdens. Currently, there is no approved therapeutic option for cNFs aside from elective surgery. The development of new therapeutic approaches for cNF will require an understanding of the cNF cellular origin that can be used to elucidate mechanisms that underpin cNF formation and growth. While biallelic inactivation of NF1 in neoplastic Schwann cells is essential for cNF formation, it is not sufficient, pointing to the critical roles of other genetic or epigenetic changes as well as extrinsic signals from other cell types in the tumor microenvironment. While the field has made significant inroads towards our understanding of these tumors, there are still gaps in our knowledge of cNF pathogenesis that could be addressed by the adoption of a systemic approach to decipher all the biological steps in cNF development from the cell of origin to tumor stage to identify the ?rate limiting step? that can be therapeutically targeted to prevent or delay cNF formation. Therefore, in this application, we propose a set specific aims to fill this knowledge gap: We will define the identity of the cNF cell of origin in mice that will guide us to identify the cells of origin for human cNF. We will next decipher how the cell of origin and the tumor microenvironment contribute to drive cNF initiation that will uncover its pathogenesis to delineate biological steps and mechanisms in tumor development as well as generating of preclinical models system that elucidate cNF biology and enable preclinical therapeutic testing.
Neurofibromas develop from a type of cell called Schwann cells which normally produce the insulating myelin sheath covering peripheral nerves. Neurofibroma can infiltrate the nerves; splay apart the individual nerve fibers and can damage their function. Patients with Neurofibroma suffer from chronic pain, numbness, and their physical impairment of vital organ or neural function can be life threatening. However, little is known about the mechanisms mediating the initiation and progression of these tumors and there is no effective medical treatment exists currently. This research proposal will fill this gap of knowledge to identify the cell of origin for these tumors to elucidate the mechanisms by which the cell of origin and the tumor microenvironment contribute to drive Neurofibroma formation, as well as to generate potential specific therapeutic targets for Neurofibroma.
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