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.

项目摘要 胶质瘤是最常见的脑癌形式。在成人和儿童中，高级神经胶质瘤是 与脑癌相关死亡的主要原因，而与小儿治疗有关的神经毒性 低级神经胶质瘤（LGGS）经常导致长期神经认知后遗症。由于这些原因，有 紧迫的需要，以更好地定义与神经胶质瘤发展和发展相关的机制 改善治疗并降低终身神经毒性。这对于患有的儿童尤其重要 神经纤维瘤病1型（NF1）癌症易感性，患有低度光途径神经胶质瘤（OPGS） 那损害了视野。这些NF1-OPG在幼儿期（平均年龄为4.5岁），在那里它们本地化 到含有视网膜神经节细胞（RGC）的轴突的视神经和/或CHIASM-神经元亚型 负责将光诱导的信号从视网膜传输到大脑。鉴于亲密关系 在这些肿瘤与视神经之间，Monje和Gutmann实验室之间的合作企业 使用身份验证的 临床前NF1视神经胶质瘤小鼠菌株在组织学上类似于其人类。在这些研究中， 我们发现肿瘤形成之前减少视网膜神经节细胞（RGC）神经元活性可防止OPG 启动，而降低的RGC神经元活性减弱了OPG的增长。另外，NF1突变体 （类似于NF1患者），但不是野生型（正常），视神经表现出增加的Neuroligin-3表达 以及对RGC活性的响应，由ADAM10裂解控制。此外，Neuroligin-3 （NLGN3）是NF1缺陷型OPG细胞的有效生长因子，NF1光学中神经素3的遗传丧失 途径胶质瘤小鼠在体内阻止肿瘤形成。最后，使用ADAM10抑制Neuroligin-3脱落 抑制剂降低了NF1-OPG的生长。基于这些令人兴奋的初步数据，我们假设NF1突变 在RGC中，神经元促进了驱动NF1启动和维护的神经素3信号传导失调 视神经胶质瘤。在此协作R01提案中，我们旨在阐明细胞内在之间的交集 肿瘤（NF1肿瘤损失）和旁分泌影响肿瘤微环境中的神经元的影响 与了解NF1儿童中这些常见脑肿瘤的发病机理有关。