Functional Genomic Dissection of Refractory Anemia

难治性贫血的功能基因组解析

基本信息

批准号：
7459616
负责人：
Benjamin Levine Ebert
金额：
$ 43.02万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7459616
关键词：
5q31 5q32 Acute Myelocytic Leukemia Address Alleles Apoptosis Biological Biological Sciences Biology Bone Marrow Diseases CD34 gene Cancer Center Candidate Disease Gene Cells Characteristics Chemicals Chromosome Arm Chromosome abnormality Chromosomes, Human, Pair 5 Chronic Myeloid Leukemia Class Classification Clinic Clinical Cloning Collection Communities Computer Analysis Custom DNA Resequencing Dana-Farber Cancer Institute Data Databases Defect Detection Development Diagnostic Disease Dissection Drug Compounding Dysmyelopoietic Syndromes Environment Erythroid Exons Gene Expression Gene Expression Profile Gene Expression Profiling Gene Mutation Generations Genes Genetic Genome Genomics Gleevec Goals Hand Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic stem cells Human Imatinib Impairment In Vitro Individual Ineffective Hematopoiesis Institutes Laboratories Ligation Location Malignant Neoplasms Maps Marrow Measurable Measurement Mediating Megakaryocytes Methods Molecular Molecular Abnormality Mutation Myelogenous Normal Cell Outcome Pathogenesis Patients Pharmaceutical Preparations Phenotype Predisposition Principal Investigator Proliferating Purpose RNA Interference Recurrence Refractory anemias Reliance Research Research Personnel Research Proposals Residual state Sampling Screening procedure Syndrome System Technology Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome Time Translating Translocation Breakpoint Tumor Suppressor Genes Tumor Suppressor Proteins Upper arm Work anticancer research base bcr-abl Fusion Proteins cancer genome chromosome 5q loss clinical phenotype comparative genomic hybridization cost cytopenia density erythroid differentiation falls functional genomics high throughput screening human cord blood CD34+ cell insight interest interstitial leukemia loss of function novel peripheral blood progenitor programs single molecule small hairpin RNA small molecule small molecule libraries tool

项目摘要

DESCRIPTION (provided by applicant): Myelodysplastic syndrome (MDS) has been long recognized as a collection of diseases characterized by ineffective hematopoiesis associated with impairment of differentiation and intra-medullary apoptosis. Moreover, patients with MDS often progress to acute myeloid leukemia (AML). The pathogenesis of MDS remains obscure, and effective therapies are lacking. One challenge is that MDS represents a diverse collection of diseases, categorized by often vague clinical criteria. One exception to this, however, is the 5q syndrome, which has distinct clinical characteristics and is associated with deletions of the long arm of chromosome 5. The disease gene for this syndrome has yet to be identified. We therefore propose here an ambitious genomics-based approach to the cloning of the 5q- syndrome disease gene, and to the discovery of small molecules that circumvent the differentiation block that is characteristic of MDS. In Aim 1, we will perform a systematic, RNA interference-based functional genomic screen in CD34+ primary hematopoietic progenitor cells to identify those genes in the critically deleted region of 5q that recapitulate the differentiation defect characteristic of MDS. In addition, we will perform fine-mapping of the 5q region using high density custom microarray comparative genomic hybridization (CGH) in order to identify patients with previously unrecognized, small deletions. Furthermore, we will utilize .a novel single-molecule sequencing method to resequence the candidate genes on 5q for mutations. In Aim 2, we will perform a high throughput gene expression-based small molecule screen using the GE-HTS method developed in our laboratory. Using this approach, we expect to identify small molecules (or drugs) capable of promoting the expansion and differentiation of hematopoietic progenitors. Such compounds would be valuable both as tool compounds with which to dissect the biology of MDS, and as potential starting points for the development of new therapies of MDS.

描述（由申请人提供）：骨髓增生异常综合征（MDS）长期以来一直被认为是一组以无效造血与分化受损和髓内细胞凋亡相关的疾病。此外，MDS 患者经常进展为急性髓系白血病 (AML)。 MDS的发病机制仍不清楚，缺乏有效的治疗方法。一个挑战是 MDS 代表了多种疾病，并按通常模糊的临床标准进行分类。然而，一个例外是 5q 综合征，它具有独特的临床特征，并且与 5 号染色体长臂缺失有关。该综合征的致病基因尚未确定。因此，我们在这里提出了一种雄心勃勃的基于基因组学的方法来克隆 5q 综合征疾病基因，并发现规避 MDS 特征的分化障碍的小分子。在目标 1 中，我们将在 CD34+ 原代造血祖细胞中进行系统的、基于 RNA 干扰的功能基因组筛选，以识别 5q 严重缺失区域中重现 MDS 分化缺陷特征的基因。此外，我们将使用高密度定制微阵列比较基因组杂交 (CGH) 对 5q 区域进行精细定位，以识别具有先前未识别的小缺失的患者。此外，我们将利用一种新颖的单分子测序方法对 5q 上的突变候选基因进行重新测序。在目标 2 中，我们将使用我们实验室开发的 GE-HTS 方法进行基于高通量基因表达的小分子筛选。使用这种方法，我们期望鉴定出能够促进造血祖细胞扩增和分化的小分子（或药物）。此类化合物既可以作为剖析 MDS 生物学的工具化合物，也可以作为开发 MDS 新疗法的潜在起点。