DEFINING RISK FACTORS FOR NF1-OPTIC GLIOMA

定义 NF1 视神经胶质瘤的危险因素

• 批准号: 9171983
• 负责人: David H Gutmann
• 金额: $ 34.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171983
• 关键词: Affect; Apoptosis; Assessment tool; Attenuated; Biological Markers; Blindness; Brain Neoplasms; Cell Death; Cell Survival; Child; Childhood; Clinical; Cyclic AMP; Development; Disease; Disease Outcome; Epidemiologic Studies; Female; Fibroblasts; Frameshift Mutation; Functional disorder; GPER gene; Gene Mutation; Generations; Genetically Engineered Mouse; Glial Fibrillary Acidic Protein; Glioma; Gonadal Steroid Hormones; Growth; Hormonal; Hormone Receptor; Human; Individual; Inherited; Intervention; Laboratories; Malignant Childhood Neoplasm; Medical; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutation; NF1 gene; Neoplasms; Neurofibromatosis 1; Neurofibromatosis Type 1 Protein; Neurological outcome; Neuronal Dysfunction; Optic Nerve; Optic Nerve Glioma; Optical Coherence Tomography; Optics; Outcome; Pathway interactions; Patients; Predisposition; Radiation; Retinal; Retinal Ganglion Cells; Risk; Risk Assessment; Risk Factors; Series; Serum; Syndrome; System; Tamoxifen; Therapeutic; Thick; Translating; Vision; Visual; Visual Acuity; Visual impairment; base; chemotherapy; clinical care; disease heterogeneity; disorder risk; experience; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; male; mutant; neurofilament; novel; novel strategies; patient population; personalized medicine; potential biomarker; preclinical study; prevent; prognostic; receptor; research study; retinal nerve fiber layer; sex; therapy outcome; tumor; virtual

Project Summary As we enter into an era of personalized medicine, it becomes increasingly important to define the factors that confer disease risk and outcome. Since these determinants cannot be easily controlled in human epidemiological studies, genetically-engineered mouse (GEM) strains provide mechanistically-tractable platforms to define the factors underlying disease heterogeneity and translate them to risk assessment tools and treatments. Pediatric low-grade brain tumors (gliomas) represent one such challenging disease with respect to predicting clinical progression, optimizing treatment, and improving neurologic outcome. In the most common inherited cause for pediatric low-grade glioma, neurofibromatosis type 1 (NF1), 15-20% of children develop optic pathway gliomas (OPGs), leading to visual decline in 30-60% of affected individuals. However, it is not currently possible to predict which child with NF1 will develop an OPG or who will experience visual decline or blindness from their tumor. Our ability to identify those children at greatest risk for OPG development and vision loss would provide important clinically-meaningful prognostic information to guide clinical care for a pre-verbal patient population in which accurate visual assessments can be challenging. Recent observations suggest that the specific germline NF1 gene mutation may be one risk factor for OPG development, whereas patient sex influences OPG-associated visual decline. In this regard, children with NF1-associated OPGs are more likely to harbor specific types of germline NF1 gene mutations (5' end frameshift mutations). In addition, we have recently shown that female children and mice with NF1 more frequently experience visual loss from their OPGs. Based on these provocative findings, we hypothesize that the particular germline NF1 gene mutation and gonadal sex hormones are independent risk factors for OPG development and progression, respectively. In this proposal, we aim to critically determine how the specific NF1 gene mutation dictates OPG formation and define the molecular basis for the observed sexually-dimorphic OPG-associated vision loss using a novel series of Nf1 GEM strains and approaches. The resulting outcomes will be leveraged to preclinically evaluate new approaches to identifying children with NF1 at risk for OPG development and vision loss as well as potential alternative therapeutic approaches for attenuating or preventing NF1-OPG-related visual decline.

项目摘要 当我们进入个性化医学时代时，定义因素变得越来越重要 赋予疾病风险和结果。由于这些决定因素不能轻易在人类中控制 流行病学研究，遗传工程小鼠（GEM）菌株提供了机械上牵引的菌株 平台来定义疾病异质性的因素并将其转化为风险评估工具 和治疗。小儿低度脑肿瘤（神经胶质瘤）代表一种具有挑战性的疾病 尊重预测临床进展，优化治疗和改善神经系统结果。最多 小儿低级神经胶质瘤，神经纤维瘤病1型（NF1）的常见遗传原因，15-20％的儿童 开发光学途径胶质瘤（OPG），导致30-60％的受影响个体的视觉下降。但是，它 目前无法预测哪个患有NF1的孩子会开发OPG或将体验视觉 肿瘤的衰落或失明。我们识别那些有最大风险OPG开发风险的孩子的能力 视力丧失将提供重要的临床预后信息，以指导临床护理 准确的视觉评估可能具有挑战性的言语前患者人群。最近的观察 表明特定种系NF1基因突变可能是OPG发育的危险因素，而 患者性别影响与OPG相关的视觉下降。在这方面，与NF1相关的儿童是 更有可能具有特定类型的种系NF1基因突变（5'末端移码突变）。此外， 我们最近表明，具有NF1的女儿和小鼠更频繁地体验到视觉丧失。 他们的OPG。基于这些挑衅性的发现，我们假设特定的种系NF1基因 突变和性腺性激素是OPG发展和进展的独立风险因素， 分别。在此提案中，我们旨在批判性地确定特定的NF1基因突变如何决定OPG 形成并定义观察到的性二态OPG相关视力丧失的分子基础 使用一系列新型NF1宝石菌株和方法。由此产生的结果将被利用 临时评估识别有NF1儿童有OPG开发和远见风险的新方法 损失以及潜在的替代治疗方法，用于衰减或预防NF1-OPG相关 视觉下降。