Neuronal Regulation of Low-Grade Gliomagenesis

低度胶质瘤发生的神经元调节

• 批准号: 10596172
• 负责人: David H Gutmann
• 金额: $ 62.57万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596172
• 关键词: Accounting; Adult; Age; Attenuated; Biology; Brain; Brain Neoplasms; Cells; Cessation of life; Child; Childhood; Darkness; Data; Development; Diagnosis; Evolution; Exhibits; Foundations; Genetic; Glioma; Gliomagenesis; Goals; Growth; Growth Factor; Histologic; Human; In Vitro; Laboratories; Light; Maintenance; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Mutant Strains Mice; NF1 gene; NF1 mutation; Neurocognitive; Neurofibromatosis 1; Neurons; Optic Chiasm; Optic Nerve; Optic Nerve Glioma; Optics; Outcome; Pathogenesis; Pathway interactions; Patients; Pediatric Neoplasm; Penetrance; Primary Brain Neoplasms; Production; Proliferating; Regulation; Retina; Retinal Ganglion Cells; Role; Signal Induction; Signal Transduction; Syndrome; Transcriptional Regulation; Tumor Suppressor Proteins; Visual impairment; cancer predisposition; cancer type; early childhood; experimental study; genetic approach; improved; in vivo; inhibitor; light deprivation; light transmission; mouse model; mutant; neoplastic cell; neuroligin 3; neuronal excitability; neurotoxicity; neurotransmission; optogenetics; paracrine; pharmacologic; pre-clinical; prevent; response; retinal axon; retinal stimulation; tumor; tumor growth; tumor microenvironment; tumorigenesis

Project Summary Gliomas comprise the most common form of brain cancer. In adults and children, high-grade gliomas are the leading cause of brain cancer-related death, whereas the neurotoxicity associated with the treatment of pediatric low-grade gliomas (LGGs) frequently results in long-term neurocognitive sequelae. For these reasons, there is a pressing need to better define the mechanisms that underlie glioma development and progression relevant to improving treatment and reducing lifelong neurotoxicity. This is especially important for children with the Neurofibromatosis type 1 (NF1) cancer predisposition who develop low-grade optic pathway gliomas (OPGs) that impair vision. These NF1-OPGs form during early childhood (mean age, 4.5 years), where they are localized to the optic nerve and/or chiasm containing the axons of retinal ganglion cells (RGCs) - the neuronal subtype responsible for transmitting light-induced signals from the retina to the brain. Given the intimate relationship between these tumors and the optic nerve, a collaborative venture between the Monje and Gutmann laboratories resulted in the identification of a key regulatory role for neurons in NF1-OPG biology using authenticated preclinical Nf1 optic glioma mouse strains that histologically resemble their human counterparts. In these studies, we found that decreasing retinal ganglion cell (RGC) neuronal activity prior to tumor formation prevents OPG initiation, while reduced RGC neuronal activity attenuates established OPG growth. In addition, Nf1 mutant (similar to patients with NF1), but not wild-type (normal), optic nerves exhibit increased neuroligin-3 expression and secretion in response to RGC activity, which is controlled by ADAM10 cleavage. Moreover, neuroligin-3 (Nlgn3) is a potent growth factor for Nf1-deficient OPG cells in vitro and genetic loss of neuroligin-3 in Nf1 optic pathway glioma mice blocks tumor formation in vivo. Lastly, inhibition of neuroligin-3 shedding using ADAM10 inhibitors reduces Nf1-OPG growth. Based on these exciting preliminary data, we hypothesize that Nf1 mutation in RGC neurons promotes dysregulated neuroligin-3 signaling that drives the initiation and maintenance of Nf1 optic glioma. In this collaborative R01 proposal, we aim to elucidate the intersection between cell-intrinsic vulnerability (NF1 tumor suppressor loss) and paracrine influences from neurons in the tumor microenvironment relevant to understanding the pathogenesis of these common brain tumors in children with NF1.

项目总结