The Role of Neuronal Activity in NF1-Associated Optic Pathway Gliomagenesis
Abstract
Optic pathway gliomas (OPGs) are low-grade tumors of the visual system that affect 15%-20% of children with NF1. These tumors, primarily affecting the nerves behind the eyes, represent a significant cause of disability in individuals with NF1, including vision loss. The tumors can also compromise the endocrine (hormone) system. Therapeutic options are limited, as traditional chemotherapy is of moderate utility and radiation therapy is associated with more complications in the setting of NF1. Understanding the factors inherent to the cells that give rise to these tumors and the interactions between cells of the visual system that promote the initiation and growth of these tumors is crucial for developing improved treatment strategies. Recently, collaborator Dr. Gutmann determined that optic pathway gliomas arise from a neural stem cell nearby the optic pathway. We have recently discovered that active neurons, such as the neurons of the retina (eye) that form the optic pathway, promote the proliferation of neural stem cells like those that give rise to optic pathway gliomas. We subsequently found that active neurons promote the proliferation and growth of other types of pediatric glioma. In this proposal, we will test the hypothesis that retinal neuronal activity promotes the formation and growth of optic pathway gliomas associated with NF1. To do this, we will modulate the activity of retinal neurons using light and an advanced neuromodulatory technology called "optogenetics" in mouse models of NF1. We will also define the growth factors secreted by active visual pathway neurons to identify new therapeutic targets for NF1-associated optic pathway glioma. The results of the proposed experiments may help children with NF1 who develop optic pathway glioma preserve vision and endocrine function and also avoid serious side effects of traditional therapies like cranial radiation. Furthermore, what we learn about NF1-associated optic pathway glioma may help children with non-NF1-associated optic pathway glioma and other low-grade gliomas of childhood. Time to clinical translation depends on the nature of the discovered targets. This work could lead to new therapies quickly (within 5 years) should drugs that target retinal neuron-optic pathway glioma cell interactions already exist and it is matter of now applying those drugs in a new way for optic pathway glioma. If entirely novel drugs need to be developed, the time frame is likely to be more on the order of 10 years or more until the work is translated to children with NF1-associated optic pathway glioma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510131
Entities
People
- Michelle Monje
Organizations
- Stanford University
- United States Army