Identifying Events and Genetic Regulators of Melanoma Progression

识别黑色素瘤进展的事件和遗传调节因子

基本信息

批准号：
7571782
负责人：
Craig Joseph Ceol
金额：
$ 9.18万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-10 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7571782
关键词：
Affect Age Aneuploidy Animals BRAF gene Benign Biological Assay Cell Cycle Cell Nucleus Cell Separation Cells Centrosome Chromosomal Gain Coupled Defect Development Diagnosis Diagnostic Disease Event Functional disorder Gene Dosage Genes Genetic Goals Human Image Incidence Lesion Malignant Neoplasms Mammalian Cell Melanocytic nevus Melanoma Cell Methods Mitosis Mole the mammal Mutation Nevi and Melanomas Oncogenes Oncogenic Pathway interactions Pharmaceutical Preparations Ploidies Polyploid Cells Polyploidy Process Protein-Serine-Threonine Kinases Receptor Protein-Tyrosine Kinases Recurrence Research Personnel Role Skin Cancer TP53 gene Testing Transgenes Transgenic Organisms Transplantation Zebrafish cancer therapy comparative genomic hybridization high throughput screening human data interest melanocyte melanoma mutant novel overexpression prognostic indicator programs therapeutic target tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The goals of this proposal are to examine the events and genetic defects that underlie melanoma formation. Melanoma is the most aggressive and lethal form of skin cancer. Most benign nevi and melanomas have mutations activating the BRAF serine/threonine kinase, suggesting that BRAF activation is an important but insufficient step in tumorigenesis. p53 pathway alterations are also implicated in melanoma formation. While many functions have been ascribed to BRAF and p53, little is known about which if any of these functions is important in transforming normal melanocytes into melanoma cells. Furthermore, additional genetic defects that contribute this process have yet to be defined. Zebrafish strains that express human oncogenic BRAF and are mutant for p53 have been created. These strains reliably develop melanomas that are histopathologically similar to those in humans. Preliminary results indicate that binucleate, polyploid melanocytes in these mutants may give rise to tumors. In Aim 1, the events of melanoma formation will be examined. Transgenic approaches in zebrafish and long-term imaging of mammalian cells in culture will be used to determine the mechanism by which BRAF causes binuclearity. Cell sorting coupled with transplantation will be employed to determine whether binucleate cells can give rise to melanomas. In Aim 2, genetic defects that contribute to melanoma formation will be identified and characterized. In preliminary studies, the Kit receptor tyrosine kinase was identified as a suppressor of melanoma onset and invasion. Activities of Kit required for its melanoma suppression will be assessed. To identify additional melanoma genetic defects, array comparative genomic hybridization (aCGH) will be used to characterize recurrent chromosomal gains and losses in these tumors. aCGH data from human and zebrafish melanomas will be used to identify candidate oncogenes that will be tested in a novel, high-throughput assay for contribution to melanoma formation. These studies may identify diagnostic and prognostic indicators of disease as well as therapeutic targets for cancer treatment.

描述（由申请人提供）：该提案的目标是检查黑色素瘤形成的事件和遗传缺陷。黑色素瘤是皮肤癌最具侵略性，最致命的形式。大多数良性NEVI和黑色素瘤都具有激活BRAF丝氨酸/苏氨酸激酶的突变，这表明BRAF激活是肿瘤发生中重要但不足的一步。 p53途径改变也与黑色素瘤形成有关。尽管许多功能已归因于BRAF和p53，但对于将正常黑色素细胞转化为黑色素瘤细胞的任何功能中的任何一个都不了解哪个功能。此外，促成该过程的其他遗传缺陷尚未定义。已经创建了表达人类致癌BRAF并为p53突变体的斑马鱼菌株。这些菌株可靠地产生了与人类相似的组织病理学相似的黑色素瘤。初步结果表明，这些突变体中的双核，多倍体黑素细胞可能会导致肿瘤。在AIM 1中，将检查黑色素瘤形成的事件。斑马鱼中的转基因方法和培养哺乳动物细胞的长期成像将用于确定BRAF引起双核性的机制。将采用与移植结合的细胞分选，以确定双核细胞是否会引起黑色素瘤。在AIM 2中，将确定和表征有助于黑色素瘤形成的遗传缺陷。在初步研究中，试剂盒受体酪氨酸激酶被确定为黑色素瘤发作和侵袭的抑制剂。将评估其抑制黑色素瘤所需的盒子活动。为了鉴定其他黑色素瘤遗传缺陷，将使用阵列比较基因组杂交（ACGH）来表征这些肿瘤中复发性染色体的增长和损失。来自人类和斑马鱼黑色素瘤的ACGH数据将用于鉴定候选癌基因，这些肿瘤基因将在新型的高通量测定中进行测试，以贡献黑色素瘤形成。这些研究可能确定疾病的诊断和预后指标以及癌症治疗的治疗靶标。