Leveraging Genetically-Engineered Mice to Optimize Pediatric Glioma Management

利用基因工程小鼠优化儿童神经胶质瘤治疗

• 批准号: 9297258
• 负责人: David H Gutmann
• 金额: $ 55.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297258
• 关键词: Affect; Assessment tool; Biocompatible Materials; Biometry; Blindness; Blood; Brain Neoplasms; Cell Culture Techniques; Cell model; Cells; Child; Child Care; Childhood; Childhood Glioma; Clinical; Clinical assessments; Collection; Computational Biology; Disease; Disease Outcome; Disease Progression; Dissection; Engineering; Epigenetic Process; Etiology; Female; Fibroblasts; Functional disorder; Gene Mutation; Genetic; Genetic screening method; Genetically Engineered Mouse; Glioma; Growth; Hormones; Human; Immune system; Individual; Inherited; International; Lead; Malignant Childhood Neoplasm; Malignant Neoplasms; Medical; Microglia; Molecular; Mouse Models of Human Cancer Consortium; Mouse Strains; Mus; Mutant Strains Mice; NF1 gene; National Cancer Institute; Neurofibromatosis 1; Neurofibromatosis Type 1 Protein; Neurologic Dysfunctions; Neurological outcome; Neuronal Dysfunction; Neurons; Optic Nerve Glioma; Optics; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Predisposition; Property; Recovery; Research Personnel; Risk Assessment; Risk Factors; Rodent; Series; Somatic Cell; Stem cells; Syndrome; Therapeutic; Translating; Vision; Visual; Visual Acuity; animal imaging; base; behavior test; cancer epidemiology; cancer type; chemotherapy; clinical practice; clinical predictors; defined contribution; design; disease heterogeneity; disorder risk; effective therapy; epidemiology study; experience; experimental study; girls; improved; individualized medicine; male; mathematical model; mouse model; neuropathology; neurosurgery; novel; personalized medicine; predict clinical outcome; prognostic; programs; protein expression; protein function; public health relevance; response; sexual dimorphism; success; therapeutic evaluation; treatment response; treatment strategy; tumor; tumor progression

 DESCRIPTION (provided by applicant): 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. Moreover, conventional chemotherapy results in disease stabilization in only 50-60% of children, and few experience improvement in their visual acuity following treatment. Currently, it is not possible to predict which child with a NF1-OPG will experience visual dysfunction (Barrier 1) and what treatments are most likely to result in tumor response and lead to visual recovery (Barrier 2). Over the past 10 years, as part of the National Cancer Institute Mouse Models of Human Cancers Consortium, we leveraged a collection of novel Nf1 GEM strains with optic glioma to establish that (1) the germline NF1 gene mutation partly determines NF1 protein expression and function, (2) female, but not male, Nf1 mutant mice with optic glioma have reduced visual acuity, (3) non-neoplastic immune system-like cells (microglia) carrying only a germline NF1 gene mutation are required for murine optic glioma formation and growth, and (4) murine optic gliomas contain glioma stem cells (optic GSCs) with unique, and potentially targetable, molecular and cellular properties. Based on these findings, we propose a systematic, team-based dissection of the factors responsible for NF1-optic glioma progression, vision loss, and therapeutic success. For this initiative, we have assembled a cross- disciplinary collaborative team to (a) define the molecular etiology for female susceptibility to OPG-induced visual decline (Aim 1), (b) assess the impact of the germline NF1 gene mutation on OPG-induced visual decline (Aim 2) as well as (c) microglia function relevant to potential stroma-directed glioma treatments (Aim 3), and (d) exploit a series of distinct GSCs from Nf1 optic glioma GEMs for developing new treatments that uniquely target the cells most responsible for maintaining the tumor (Aim 4). Collectively, these studies have immediate translatability to the human condition, given the wide clinical availability of NF1 genetic testing, recent advances in rapid cellular reprograming, and the existence of two large international consortia with proven expertise in NF1-OPG clinical assessment and therapeutic evaluation.

 描述（由申请人提供）：随着我们进入个性化医疗时代，定义赋予疾病风险和结果的因素变得越来越重要。由于这些决定因素在人类流行病学研究中不易控制，因此基因工程小鼠（GEM）品系提供了一个机械上易于处理的平台来定义疾病异质性的潜在因素，并将其转化为风险评估工具和治疗方法。儿童低级别脑肿瘤（神经胶质瘤）代表了一种在预测临床进展、优化治疗和改善神经功能结局方面具有挑战性的疾病。在儿童低级别胶质瘤的最常见遗传原因中，1型神经纤维瘤病（NF 1），15-20%的儿童发展为视路胶质瘤（OPG），导致30-60%受影响个体的视力下降。此外，常规化疗仅在50-60%的儿童中导致疾病稳定，并且在治疗后很少有视力改善。目前，尚无法预测哪种NF 1-OPG患儿将出现视觉功能障碍（屏障1），以及何种治疗最有可能导致肿瘤缓解并导致视力恢复（屏障2）。在过去的10年里，作为美国国家癌症研究所人类癌症小鼠模型联盟的一部分，我们利用了一系列具有视神经胶质瘤的新型Nf 1 GEM菌株，以确定（1）种系NF 1基因突变部分决定了NF 1蛋白的表达和功能，（2）雌性而非雄性，具有视神经胶质瘤的Nf 1突变小鼠视力下降，（3）鼠视神经胶质瘤形成和生长需要仅携带种系NF 1基因突变的非肿瘤性免疫系统样细胞（小胶质细胞），和（4）鼠视神经胶质瘤含有具有独特的和潜在的靶向分子和细胞特性的胶质瘤干细胞（视神经GSC）。基于这些发现，我们提出了一个系统的，以团队为基础的解剖的因素负责NF 1视神经胶质瘤的进展，视力丧失，和治疗成功。为此，我们组建了一个跨学科合作团队，以（a）确定女性对OPG诱导的视力下降易感性的分子病因学（目标1），（B）评估生殖系NF 1基因突变对OPG诱导的视力下降的影响（目标2）以及（c）与潜在基质定向胶质瘤治疗相关的小胶质细胞功能（目标3），和（d）利用来自Nf 1视神经胶质瘤GEM的一系列不同的GSC来开发新的治疗方法，所述新的治疗方法独特地靶向最负责维持肿瘤的细胞（目的4）。总的来说，这些研究可以直接应用于人类疾病，因为NF 1基因检测的临床应用广泛，快速细胞重编程的最新进展，以及两个大型国际财团在NF 1-OPG临床评估和治疗评价方面的专业知识。

项目成果

Exploring the genetic basis for clinical variation in neurofibromatosis type 1.

探索 1 型神经纤维瘤病临床变异的遗传基础。

• DOI: 10.1080/14737175.2016.1189329
• 发表时间: 2016
• 期刊: Expert review of neurotherapeutics
• 影响因子: 4.3
• 作者: Gutmann,DavidH

Variability of Betweenness Centrality and Its Effect on Identifying Essential Genes.

中间性中心的变异性及其对识别基本基因的影响。

• DOI: 10.1007/s11538-018-0526-z
• 发表时间: 2019-09
• 期刊: Bulletin of mathematical biology
• 影响因子: 3.5
• 作者: Durón C;Pan Y;Gutmann DH;Hardin J;Radunskaya A
• 通讯作者: Radunskaya A