Defining the Role of Neuronal Activity on the Initiation and Growth of Neurofibromatosis Type 1 (NF1)-Associated Optic Glioma
Abstract
Rationale: Optic gliomas are brain tumors of the visual system that affect 15-20% of children with neurofibromatosis type 1 (NF1). These tumors primarily affect the nerves behind the eyes and cause disabilities such as vision loss and malfunction of the endocrine (hormone) system. To date, therapeutic options are limited for children with NF1-associated optic gliomas; chemotherapy does not achieve satisfactory vision improvement, and radiation is associated with more complications or malignancies. Like other solid tumors, optic glioma represents an ecosystem where tumor cells “hijack” the normal developmental machineries provided by surrounding cells to establish a unique tumor microenvironment. Understanding how optic glioma cells interact with their surrounding cells, for example neurons, to initiate and maintain the tumor ecosystem is critical for developing new treatment strategies for NF1-associated optic glioma. Recently, the laboratory of my mentor, Dr. Michelle Monje-Deisseroth, has demonstrated, for the first time, that the normal daily activity of neuronal cells promotes the growth some brain tumors. Since the optic glioma ecosystem consists of neurons from the visual system, I propose to determine whether and how the visual system neuronal activity promotes the formation and growth of NF1-associated optic glioma. Objective: In this study, I will test the hypothesis that the activity of the visual system neuronal cells promotes the formation and growth of NF1-associated optic gliomas. To do this, I will leverage genetically engineered mice (the expertise of my co-mentor, Dr. David Gutmann) that mimic the genetics of NF1 patients and develop optic glioma consistently during a trackable time window. I will modulate the activity of visual system neurons in these mice using both light and an advanced neuromodulatory technology named optogenetics, which activates neurons at a specific location and time. I will also determine the role of growth factors produced by these active visual system neurons on the formation and growth of NF1-assocaited optic glioma. Both candidate-based and unbiased approaches will be applied to identify new therapeutic targets for NF1-associated optic gliomas. Applicability: The findings of this proposed research may help develop new drug targets and therapeutic strategies for children with NF1-associated optic glioma. The new treatments will help slow down or prevent the development of optic gliomas, while preserving vision and endocrine function in NF1 patients. Time to clinical translation of the research findings will depend on the availability of drugs for the identified targets. If a drug has been developed for the target and has been proven for clinical use, this research can be translated to new therapies quickly, typically within 5 years. One the other hand, if novel drugs need to be developed for the targets, translation of the research findings to clinical use will take 10 years or more. Contributions: In addition to developing new therapeutic strategies for NF1-associated optic glioma, our findings from this study may help children with non-NF1-assocaited (sporadic) optic glioma and other low-grade gliomas in general. Furthermore, the research plan proposed in this study can be applied to identify new drug targets for other NF-associated nervous system tumors and neurological diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910260
Entities
People
- Yuan Pan
Organizations
- Stanford University
- United States Army