Neuronal Regulation of Low-Grade Gliomagenesis

低度胶质瘤发生的神经元调节

• 批准号: 10412883
• 负责人: David H Gutmann
• 金额: $ 65.72万
• 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/10412883
• 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; Life; 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 Nerve; Optic Nerve Glioma; Optics; Pathogenesis; Pathway interactions; Patients; Pediatric Neoplasm; Penetrance; Pharmacology; Primary Brain Neoplasms; Production; Regulation; Retina; Retinal Ganglion Cells; Role; Signal Transduction; Syndrome; Transcriptional Regulation; Tumor Suppressor Proteins; Visual impairment; base; cancer predisposition; cancer type; early childhood; experimental study; genetic approach; improved; in vivo; inhibitor; light deprivation; mouse model; mutant; neoplastic cell; neuroligin 3; neuronal excitability; neurotoxicity; neurotransmission; optogenetics; paracrine; pre-clinical; prevent; response; retinal axon; retinal stimulation; therapy outcome; 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.

项目摘要 神经胶质瘤是脑癌中最常见的一种。在成人和儿童中，高级别胶质瘤是 脑癌相关死亡的主要原因，而与儿童治疗相关的神经毒性 低级别神经胶质瘤（LGG）经常导致长期的神经认知后遗症。由于这些原因， 迫切需要更好地确定神经胶质瘤发展和进展的机制， 改善治疗并减少终身神经毒性。这对患有自闭症的儿童尤其重要。 神经纤维瘤病1型（NF 1）癌症易感性发展为低级别视神经通路胶质瘤（OPG） 会损害视力这些NF 1-OPG在幼儿期（平均年龄4.5岁）形成， 至包含视网膜神经节细胞（RGC）轴突的视神经和/或视交叉-神经元亚型 负责将光诱导信号从视网膜传递到大脑。考虑到你和他的亲密关系 Monje和Gutmann实验室的合作项目， 结果发现，使用经鉴定的神经元在NF 1-OPG生物学中的关键调节作用， 临床前Nf 1视神经胶质瘤小鼠品系在组织学上类似于它们的人类对应物。在这些研究中， 我们发现，在肿瘤形成之前，降低视网膜神经节细胞（RGC）神经元的活性， 启动，而减少RGC神经元活性减弱建立OPG生长。此外，Nf 1突变体 （类似于NF 1患者），而非野生型（正常），视神经表现出增加的神经连接素-3表达 和响应RGC活性的分泌，其由ADAM 10切割控制。此外，神经连接素-3 （Nlgn 3）是体外Nf 1缺陷OPG细胞的有效生长因子和Nf 1视神经中神经连接素-3的遗传丢失 通路胶质瘤小鼠体内阻断肿瘤形成。最后，使用ADAM 10抑制神经连接素-3脱落 抑制剂减少Nf 1-OPG生长。基于这些令人兴奋的初步数据，我们假设Nf 1突变 在RGC神经元中，促进神经连接素-3信号转导失调，驱动Nf 1的启动和维持 视神经胶质瘤在这个合作的R 01提案中，我们的目标是阐明细胞-内在 肿瘤微环境中神经元的脆弱性（NF 1肿瘤抑制因子丢失）和旁分泌影响 相关的了解这些常见的脑肿瘤与NF 1儿童的发病机制。