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
基本信息
- 批准号:9297258
- 负责人:
- 金额:$ 55.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAssessment toolBiocompatible MaterialsBiometryBlindnessBloodBrain NeoplasmsCell Culture TechniquesCell modelCellsChildChild CareChildhoodChildhood GliomaClinicalClinical assessmentsCollectionComputational BiologyDiseaseDisease OutcomeDisease ProgressionDissectionEngineeringEpigenetic ProcessEtiologyFemaleFibroblastsFunctional disorderGene MutationGeneticGenetic screening methodGenetically Engineered MouseGliomaGrowthHormonesHumanImmune systemIndividualInheritedInternationalLeadMalignant Childhood NeoplasmMalignant NeoplasmsMedicalMicrogliaMolecularMouse Models of Human Cancer ConsortiumMouse StrainsMusMutant Strains MiceNF1 geneNational Cancer InstituteNeurofibromatosis 1Neurofibromatosis Type 1 ProteinNeurologic DysfunctionsNeurological outcomeNeuronal DysfunctionNeuronsOptic Nerve GliomaOpticsOutcomePathogenesisPathway interactionsPatientsPharmacologyPhenotypePredispositionPropertyRecoveryResearch PersonnelRisk AssessmentRisk FactorsRodentSeriesSomatic CellStem cellsSyndromeTherapeuticTranslatingVisionVisualVisual Acuityanimal imagingbasebehavior testcancer epidemiologycancer typechemotherapyclinical practiceclinical predictorsdefined contributiondesigndisease heterogeneitydisorder riskeffective therapyepidemiology studyexperienceexperimental studygirlsimprovedindividualized medicinemalemathematical modelmouse modelneuropathologyneurosurgerynovelpersonalized medicinepredict clinical outcomeprognosticprogramsprotein expressionprotein functionpublic health relevanceresponsesexual dimorphismsuccesstherapeutic evaluationtreatment responsetreatment strategytumortumor progression
项目摘要
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
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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:
- 影响因子:4.3
- 作者:Gutmann,DavidH
- 通讯作者: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:
- 影响因子:3.5
- 作者:Durón C;Pan Y;Gutmann DH;Hardin J;Radunskaya A
- 通讯作者:Radunskaya A
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
David H Gutmann其他文献
Pediatric low-grade glioma: State-of-the-art and ongoing challenges.
儿科低级别胶质瘤:最先进的技术和持续的挑战。
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:15.9
- 作者:
J. Fangusaro;D. Jones;R. Packer;David H Gutmann;T. Milde;O. Witt;Sabine Mueller;Michael J Fisher;J. Hansford;U. Tabori;Darren R Hargrave;P. Bandopadhayay - 通讯作者:
P. Bandopadhayay
David H Gutmann的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('David H Gutmann', 18)}}的其他基金
Neuronal Regulation of Low-Grade Gliomagenesis
低度胶质瘤发生的神经元调节
- 批准号:
10412883 - 财政年份:2022
- 资助金额:
$ 55.15万 - 项目类别:
Neuronal Regulation of Low-Grade Gliomagenesis
低度胶质瘤发生的神经元调节
- 批准号:
10596172 - 财政年份:2022
- 资助金额:
$ 55.15万 - 项目类别:
Defining the Mechanistic Basis for Neurofibromatosis-1 Nervous System Disease Heterogeneity
定义神经纤维瘤病-1神经系统疾病异质性的机制基础
- 批准号:
10533079 - 财政年份:2016
- 资助金额:
$ 55.15万 - 项目类别:
Defining the Mechanistic Basis for Neurofibromatosis-1 Nervous System Disease Heterogeneity
定义神经纤维瘤病-1神经系统疾病异质性的机制基础
- 批准号:
10534120 - 财政年份:2016
- 资助金额:
$ 55.15万 - 项目类别:
Defining the Mechanistic Basis for Neurofibromatosis-1 Nervous System Disease Heterogeneity
定义神经纤维瘤病-1神经系统疾病异质性的机制基础
- 批准号:
10062526 - 财政年份:2016
- 资助金额:
$ 55.15万 - 项目类别:
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 - 财政年份:2016
- 资助金额:
$ 55.15万 - 项目类别:
DEFINING RISK FACTORS FOR NF1-OPTIC GLIOMA
定义 NF1 视神经胶质瘤的危险因素
- 批准号:
9333268 - 财政年份:2016
- 资助金额:
$ 55.15万 - 项目类别:
Defining the Mechanistic Basis for Neurofibromatosis-1 Nervous System Disease Heterogeneity
定义 Neurophimatosis-1 神经系统疾病异质性的机制基础
- 批准号:
10302300 - 财政年份:2016
- 资助金额:
$ 55.15万 - 项目类别:
DEFINING RISK FACTORS FOR NF1-OPTIC GLIOMA
定义 NF1 视神经胶质瘤的危险因素
- 批准号:
9751813 - 财政年份:2016
- 资助金额:
$ 55.15万 - 项目类别:
相似海外基金
The potential of using student-conducted ethnographic research as a formative assessment tool in CLIL and EMI courses
在 CLIL 和 EMI 课程中使用学生进行的民族志研究作为形成性评估工具的潜力
- 批准号:
24K04145 - 财政年份:2024
- 资助金额:
$ 55.15万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
I-Corps: Remote monitoring and assessment tool for spinal care patients
I-Corps:脊柱护理患者的远程监测和评估工具
- 批准号:
2321802 - 财政年份:2023
- 资助金额:
$ 55.15万 - 项目类别:
Standard Grant
SBIR Phase I: PenEEG: An Objective Assessment Tool for Concussion and Recovery Management
SBIR 第一阶段:PenEEG:脑震荡和恢复管理的客观评估工具
- 批准号:
2304353 - 财政年份:2023
- 资助金额:
$ 55.15万 - 项目类别:
Standard Grant
Developing a new risk and needs assessment tool for young people who have displayed harmful sexual behaviour
为表现出有害性行为的年轻人开发新的风险和需求评估工具
- 批准号:
2886506 - 财政年份:2023
- 资助金额:
$ 55.15万 - 项目类别:
Studentship
Development of the Dementia-Friendly Environmental Assessment Tool for Japanese care and nursing homes
为日本护理院和疗养院开发痴呆症友好型环境评估工具
- 批准号:
22KJ0474 - 财政年份:2023
- 资助金额:
$ 55.15万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Implementation of an impact assessment tool to optimize responsible stewardship of genomic data in the cloud
实施影响评估工具以优化云中基因组数据的负责任管理
- 批准号:
10721762 - 财政年份:2023
- 资助金额:
$ 55.15万 - 项目类别:
I-Corps: Sensor-based frailty assessment tool using a smart watch
I-Corps:使用智能手表的基于传感器的虚弱评估工具
- 批准号:
2311611 - 财政年份:2023
- 资助金额:
$ 55.15万 - 项目类别:
Standard Grant
Injury prevention for rugby-related concussion: development of a comprehensive tackle assessment tool
橄榄球相关脑震荡的伤害预防:开发综合铲球评估工具
- 批准号:
23K16737 - 财政年份:2023
- 资助金额:
$ 55.15万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Development of a diagnostic assessment tool and training app for dyscaliculia to apply in medical treatment and education.
开发计算障碍诊断评估工具和培训应用程序,以应用于医疗和教育。
- 批准号:
23K02570 - 财政年份:2023
- 资助金额:
$ 55.15万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Clinical Grip Training and Assessment Tool for Rheumatoid Arthritis
类风湿关节炎的临床握力训练和评估工具
- 批准号:
10050499 - 财政年份:2023
- 资助金额:
$ 55.15万 - 项目类别:
Collaborative R&D