Modifiers of Tumor Susceptibility in Murine Neuroblastoma

小鼠神经母细胞瘤肿瘤易感性的调节因素

基本信息

批准号：
7372323
负责人：
WILLIAM A WEISS
金额：
$ 33.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-15 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7372323
关键词：
11q 14q 17q 18q 1p36 20q Abdomen Actins Affect Age-Months Alleles Allelic Imbalance Animals Antineoplastic Agents Appendix Automobile Driving Back Backcrossings Bacterial Artificial Chromosomes Base Pairing Beta-glucuronidase Biological Brain Breeding CMV promoter Cancer Model Candidate Disease Gene Carcinoma Caspase Gene Cell Line Cells Characteristics Chest Chickens Child Childhood Chromosomal Gain Chromosome Deletion Chromosome Mapping Chromosomes Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 11 Chromosomes, Human, Pair 2 Chromosomes, Human, Pair 5 Classification Cluster Analysis Colon Complex DNA DNA Transposons Data Data Analyses Data Set Development Diagnosis Diagnostic Neoplasm Staging Diploidy Disease Disruption Distal Drug Design Electron Microscopy Elements Engineering Enhancers Epigenetic Process Event FVB/N Mouse Figs - dietary Frameshift Mutation Frequencies Gene Activation Gene Mutation Gene-Modified Genes Genetic Genetic Markers Genetic Models Genetic Polymorphism Genetic Screening Genome Genomic Instability Genomics Genus Cola Germ Lines Germ-Line Mutation Grant Health Hematopoietic Neoplasms Homeobox Genes Human Human Biology Human Chromosomes Hybridization Array Hypercapnic respiratory failure Imatinib In Vitro Inbred BALB C Mice Inbred Strains Mice Incidence Individual Inherited Insertional Mutagenesis Intercept Intestines Knock-in Mouse Knock-out Knowledge Laboratories Laboratory mice Lead Lesion Letters Location Loss of Heterozygosity MYCN gene Malignant - descriptor Malignant Neoplasms Maps Mediating Methods Methylation Microscopic Modeling Molecular Molecular Abnormality Moloney Leukemia Virus Mouse Strains Mus Mutagens Mutation N-Myc Protein Neoplasm Metastasis Neural Crest Neuroblastoma Neuron-Specific Enolase Neurons Neurosecretory Granule Neurotrophic Tyrosine Kinase Receptor Type 1 Numbers Oncogenes Oncogenic Organ Parents Pathogenesis Pathway interactions Patients Pattern Pediatric Neoplasm Penetrance Peripheral Phenotype Phospholipase Plasmacytoma Play Point Mutation Polyadenylation Polymerase Chain Reaction Population Positioning Attribute Predisposition Process Property Proto-Oncogenes Purpose RNA Splicing Rate Rattus Reagent Recurrence Relative (related person)Reporting Research Research Personnel Resistance Resolution Resources Retroviridae Risk Roche brand of trastuzumab Role Sampling Screening procedure Signal Transduction Site Skin Carcinoma Sleeping Beauty Solid Neoplasm Somatic Cell Somatic Mutation Staining method Stains Stem cells Structure Structure of superior cervical ganglion Susceptibility Gene Synaptophysin Syndrome Synteny System Technology Testing Therapeutic Agents Tissues Transcript Transgenes Transgenic Mice Transgenic Organisms Transposase Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Tissue Tumor stage Tyrosine 3-Monooxygenase Validation Virus Western Blotting angiogenesis aurora-A kinase base cancer cell cell transformation chromosome 1 gain chromosome 11 gain chromosome 5 loss comparative genomic hybridization gain of function gain of function mutation gene discovery genetic analysis genetic manipulation in vivo interest islet loss of function loss of function mutation malignant breast neoplasm mammary tumor virus mouse genome mouse model neoplastic cell neurotrophic factor novel novel therapeutics outcome forecast p19ARF pressure promoter therapeutic target tool trait transcription factor tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma, a tumor of peripheral neural crest origin, is a common and lethal tumor of childhood. Amplification of the transcription factor MYCN occurs frequently in this tumor, and correlates with advanced disease. We generated a transgenic mouse model for high-risk neuroblastoma by directing expression of a MYCN transgene to the peripheral neural crest, under control of the Tyrosine Hydroxylase (TH) promoter. Genetic analyses identified conserved genetic changes between human and murine tumors, and argue that mice transgenic for TH-MYCN represent an important genetic model for childhood neuroblastoma. We hypothesize that the additional genetic and epigenetic lesions which contribute to neuroblastoma formation in the mouse will be in genes relevant to neuroblastoma in children. The long term objective of this application is to identify genetic and epigenetic changes in murine and human neuroblastoma. Genes identified in this study may reveal novel mechanisms and pathways relevant to human MYCN-amplified neuroblastoma, ultimately leading to novel therapeutic targets. Strains of mice differ in susceptibility to tumors. Mice transgenic for TH-MYCN in strain FVB/N do not develop tumors, nearly all transgenic mice in strain 129/SvJ die of tumors by 4 months of age, and 129/SvJ FVB/N F1 mice show 4% penetrance. These observations suggest that structural or epigenetic changes in germ line modifier genes differ between strains, interact with Mycn, and underlie the differences in susceptibility between strains. These strain-specific differences provide a critical resource to identify secondary genetic and epigenetic events important in both murine and human neuroblastoma. We propose to mobilize a powerful insertional mutagen, the vertebrate Sleeping Beauty (SB) transposon, and to combine use of somatic insertional mutagenesis with comparative genomic hybridization and modifier genetics to identify genes that influence susceptibility to tumors in murine neuroblastoma. Aim 1 uses SB transposon-based insertional mutagenesis to accelerate oncogenic mutations and to increase penetrance of tumors in F1 mice. Aim 2 applies array-based comparative genomic hybridization to characterize copy-number abnormalities in both spontaneous and transposon-induced tumors in F1 mice, to characterize strain-specific methylation patterns, and to identify epigenetic changes in tumors. Aim 3 validates and characterizes candidate genes in-vitro and in-vivo, prioritizing based on the involvement of specific candidate genes in human neuroblastoma.Narrative: Neuroblastoma is a common and frequently lethal tumor of children, for which current therapies are often ineffective. The long term objective of this application is to use a mouse model for neuroblastoma developed in our laboratory to identify genes important to the development of tumors in mice and in children with this disease. Genes identified in this study are likely to reveal novel mechanisms and pathways relevant to human neuroblastoma, ultimately leading to novel therapeutic targets.

描述（由申请人提供）：神经母细胞瘤是一种起源于周围神经嵴的肿瘤，是儿童期常见且致命的肿瘤。转录因子 MYCN 的扩增经常发生在这种肿瘤中，并且与晚期疾病相关。我们通过将 MYCN 转基因在酪氨酸羟化酶 (TH) 启动子的控制下表达至周围神经嵴，建立了高危神经母细胞瘤转基因小鼠模型。遗传分析发现了人类和小鼠肿瘤之间保守的遗传变化，并认为 TH-MYCN 转基因小鼠代表了儿童神经母细胞瘤的重要遗传模型。我们假设导致小鼠神经母细胞瘤形成的额外遗传和表观遗传损伤将存在于与儿童神经母细胞瘤相关的基因中。该应用的长期目标是识别小鼠和人类神经母细胞瘤的遗传和表观遗传变化。本研究中鉴定的基因可能揭示与人类 MYCN 扩增神经母细胞瘤相关的新机制和途径，最终产生新的治疗靶点。不同品系的小鼠对肿瘤的易感性不同。 FVB/N 品系中的 TH-MYCN 转基因小鼠不会产生肿瘤，129/SvJ 品系中几乎所有转基因小鼠在 4 个月大时死于肿瘤，而 129/SvJ FVB/N F1 小鼠显示出 4% 的外显率。这些观察结果表明，种系修饰基因的结构或表观遗传变化在菌株之间存在差异，与 Mycn 相互作用，并且是菌株之间易感性差异的基础。这些菌株特异性差异为识别小鼠和人类神经母细胞瘤中重要的次生遗传和表观遗传事件提供了关键资源。我们建议利用一种强大的插入诱变剂，即脊椎动物睡美人（SB）转座子，并将体细胞插入诱变与比较基因组杂交和修饰遗传学相结合，以确定影响小鼠神经母细胞瘤肿瘤易感性的基因。目标 1 使用基于 SB 转座子的插入诱变来加速致癌突变并增加 F1 小鼠肿瘤的外显率。目标 2 应用基于芯片的比较基因组杂交来表征 F1 小鼠自发肿瘤和转座子诱导肿瘤的拷贝数异常，表征菌株特异性甲基化模式，并识别肿瘤中的表观遗传变化。目标 3 在体外和体内验证和表征候选基因，并根据人类神经母细胞瘤中特定候选基因的参与情况确定优先级。叙述：神经母细胞瘤是一种常见且经常致命的儿童肿瘤，目前的治疗方法通常无效。该应用的长期目标是使用我们实验室开发的神经母细胞瘤小鼠模型来识别对患有这种疾病的小鼠和儿童肿瘤发展重要的基因。这项研究中确定的基因可能会揭示与人类神经母细胞瘤相关的新机制和途径，最终导致新的治疗靶点。