Genomics of myelodysplastic syndromes

骨髓增生异常综合征的基因组学

• 批准号: 7120570
• 负责人: TIMOTHY A GRAUBERT
• 金额: $ 52.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120570
• 关键词: artificial chromosomes; bone marrow disorder; comparative genomic hybridization; functional /structural genomics; gene mutation; high throughput technology; human tissue; laboratory mouse; microarray technology; neoplasm /cancer genetics; nucleic acid sequence; preneoplastic state

The myelodysplastic syndromes (MDS) are a heterogenous group of disorders characterized by clonal expansion of hematopoietic cells. Cytopenias and transformation to acute myeloid leukemia are important sequelae of MDS. The genetic basis of these disorders is poorly understood. The longterm goal of this project is to identify and characterize new mutations that are important for MDS initiation and progression. We propose to conduct a large-scale study of the genomics of MDS, utilizing high-throughput resequencing and array-based comparative genomic hybridization to identify novel genetic changes in samples from patients with MDS. We have also produced a unique mouse model of alkylator-induced MDS that will complement the search for mutations that are important for human MDS. We have several key resources available that make this project feasible, including a bank of matched tumor and germline (skin) samples from MDS patients, a close collaboration with the Washington University Genome Sequencing Center, prevalidated primers for all the genes selected for resequencing, and custom-produced bacterial artificial chromosome (BAG) arrays representing the complete tiling paths for the mouse and human genomes. With these resources in hand, we propose the following specific aims: Specific Aim 1: We will utilize highthroughput DMA sequencing and comparative genomic hybridization to identify genetic changes in samples from patients with myelodysplastic syndromes. Specific Aim 2: We will utilize a mouse model of t-MDS to identify and characterize novel mutations associated with the development of myelodysplastic syndromes. These Aims are complementary and are structured to provide independent validation for the mutations we find. Although the goals of this project are primarily mutation discovery, we will utilize standard in vitro and in vivo assays to confirm the biological consequences of the mutations we discover. All genetic data that we obtain in these studies will be deposited in publicly accessible databases in a format that will be useful to other investigators. Lay Audience Summary: We propose to use several unique resources available at our institution to discover new information about the genetic basis of the myelodysplastic syndromes. These findings should improve our ability to predict the prognosis of patients with MDS and provide a rational basis for designing specific therapies that are more effective and less toxic.

骨髓增生异常综合征(MDS)是一组以造血细胞克隆性增殖为特征的异质性疾病。细胞减少和向急性髓系白血病转化是MDS的重要后遗症。人们对这些疾病的遗传基础知之甚少。该项目的长期目标是识别和表征对MDS的启动和进展至关重要的新突变。我们建议对MDS的基因组学进行大规模研究，利用高通量重测序和基于阵列的比较基因组杂交来识别MDS患者样本中的新基因变化。我们还制造了一种独特的烷化剂诱导MDS的小鼠模型，这将补充对人类MDS重要的突变的寻找。我们有几个使该项目可行的关键资源，包括来自MDS患者的匹配肿瘤和胚系(皮肤)样本库，与华盛顿大学基因组测序中心的密切合作，为重新测序选择的所有基因的预验证引物，以及定制的代表小鼠和人类基因组完整拼接路径的细菌人工染色体(BAG)阵列。有了这些资源，我们提出了以下具体目标：具体目标1：我们将利用高通量DMA测序和比较基因组杂交来鉴定骨髓增生异常综合征患者样本中的基因变化。具体目标2：我们将利用t-MDS的小鼠模型来识别和表征与骨髓增生异常综合征的发展相关的新突变。这些目标是相辅相成的，旨在为我们发现的突变提供独立的验证。虽然这个项目的目标主要是发现突变，但我们将利用标准的体外和体内测试来确认我们发现的突变的生物学后果。我们在这些研究中获得的所有基因数据将以对其他研究人员有用的格式存放在公众可访问的数据库中。外行观众总结：我们建议使用我们机构提供的几个独特的资源来发现关于骨髓增生异常综合征的遗传学基础的新信息。这些发现应该会提高我们预测MDS患者预后的能力，并为设计更有效、毒性更小的特定治疗方法提供合理的基础。