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Use of comparative genomics to identify novel regulators of melanoma progression

使用比较基因组学来识别黑色素瘤进展的新调节因子

基本信息

批准号：
9294953
负责人：
Craig Joseph Ceol
金额：
$ 35.59万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294953
关键词：
American Area Automobile Driving BRAF gene Benign Biological Assay Biology Candidate Disease Gene Catalogs Cell Count Cells Clinical Combined Modality Therapy Comparative Study Copy Number Polymorphism Cultured Cells DNA Sequence Alteration Data Defect Development Diagnosis Diagnostic Disease Drug Targeting Drug resistance Ectopic Expression Embryonic Development Epigenetic Process Family Gene Dosage Genes Genome Genomics Human Incidence Individual Knowledge Ligands Maintenance Malignant Neoplasms Melanoma Cell Modeling Mole the mammal Mutation Nevus Oncogenes Other Genetics Pathway interactions Patients Pattern Pharmacotherapy Process Prognostic Marker Proliferating Protein-Serine-Threonine Kinases Recurrence Regulation Relapse Retrospective Studies Role Route Signal Transduction Skin Cancer Testing Therapeutic Variant Zebrafish cancer genome cancer genomics cancer type comparative comparative genomics gain of function mutation growth differentiation factor 6 inhibitor/antagonist insight killings melanocyte melanoma mutant neoplastic cell new technology novel outcome forecast overexpression public health relevance restraint screening therapeutic target therapy design tumor tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Our studies seek to define genetic changes that drive progression of melanoma, the most aggressive and deadliest skin cancer. New technologies have yielded a wealth of data describing the genomes of cancers. These studies are retrospective. They offer a catalog of defects present in individual cancers but do not discriminate between tumor-promoting genomic changes and those changes that arose incidentally during tumor progression. Functional studies are necessary to draw this distinction, and in many cancers the list of candidate genomic changes can be quite large. To parse through changes in gene copy number variation we use cross-species comparisons and functional studies with a conserved zebrafish melanoma model. Since some of the genomic changes involved in melanoma progression are seen in other cancers, our studies may provide broader insights into cancer development. The genetic changes we define may be useful as diagnostic and prognostic indicators of disease as well as therapeutic targets for melanoma and potentially other types of cancer. The two areas of study in this project are: 1. Define gene copy number changes that are shared between human and zebrafish melanomas, and use functional screening to identify new melanoma genes. Mechanisms of melanoma formation are conserved between zebrafish and humans. By determining genomic alterations common to zebrafish and human melanomas we can uncover new genes and mechanisms involved in melanomagenesis. 2. Examine the BMP-family ligand GDF6 for its roles in melanoma progression and melanocyte development. The comparative studies above have already identified an excellent candidate melanoma gene, GDF6. This BMP-family ligand is recurrently amplified and overexpressed in human and zebrafish melanomas, and its expression pattern during embryogenesis suggests a role in regulation of melanocyte development. We will assess how GDF6, and BMP signaling in general, participate in melanoma formation, perhaps by regulating the differentiation and proliferation of melanocytes.

描述（由申请人提供）：我们的研究旨在确定驱动黑色素瘤进展的遗传变化，黑色素瘤是最具侵略性和最致命的皮肤癌。新技术已经产生了大量描述癌症基因组的数据。这些研究是回顾性的。他们提供了个体癌症中存在的缺陷目录，但没有区分肿瘤促进基因组变化和肿瘤进展过程中偶然发生的变化。功能研究对于区分这种差异是必要的，并且在许多癌症中，候选基因组变化的列表可能相当大。为了解析基因拷贝数变异的变化，我们使用保守的斑马鱼黑色素瘤模型进行跨物种比较和功能研究。由于参与黑色素瘤进展的一些基因组变化在其他癌症中也有发现，我们的研究可能为癌症发展提供更广泛的见解。我们定义的遗传变化可能是有用的疾病的诊断和预后指标，以及黑色素瘤和潜在的其他类型的癌症的治疗靶点。本项目研究的两个方面是：1.定义人类和斑马鱼黑色素瘤之间共有的基因拷贝数变化，并使用功能筛选来识别新的黑色素瘤基因。黑色素瘤形成的机制在斑马鱼和人类之间是保守的。通过确定斑马鱼和人类黑色素瘤共同的基因组改变，我们可以发现参与黑色素瘤发生的新基因和机制。2.检查BMP家族配体GDF6在黑色素瘤进展和黑色素细胞发育中的作用。上述比较研究已经确定了一个优秀的候选黑色素瘤基因，GDF6。这种BMP家族配体在人类和斑马鱼黑色素瘤中反复扩增和过表达，其在胚胎发生过程中的表达模式表明在调节黑色素细胞发育中的作用。我们将评估GDF6和BMP信号一般如何参与黑色素瘤的形成，可能是通过调节黑色素细胞的分化和增殖。