Functional Genomic Dissection of Refractory Anemia

难治性贫血的功能基因组解析

• 批准号: 7280771
• 负责人: TODD R. GOLUB
• 金额: $ 41.84万
• 依托单位: DANA-FARBER CANCER INST
• 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/7280771
• 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

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疾病，其特征是无效的造血功能与分化障碍和髓内细胞凋亡相关。此外，MDS患者往往进展为急性髓系白血病(AML)。MDS的发病机制尚不清楚，缺乏有效的治疗方法。一个挑战是，MDS代表了一系列不同的疾病，根据往往模糊的临床标准进行分类。然而，5q综合征是一个例外，它具有明显的临床特征，与5号染色体长臂的缺失有关。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，并发现能够绕过MDS特有的分化障碍的小分子。在目标1中，我们将在CD34+原始造血祖细胞中进行系统的、基于RNA干扰的功能基因组筛选，以确定那些位于5q关键缺失区域的基因，这些基因概括了MDS的分化缺陷特征。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，以识别以前未识别的小缺失患者。此外，我们将利用一种新的单分子测序方法对5q上的候选基因进行重新排序以寻找突变。在目标2中，我们将使用我们实验室开发的GE-HTS方法进行基于基因表达的高通量小分子筛选。使用这种方法，我们希望能够识别能够促进造血祖细胞扩增和分化的小分子(或药物)。这些化合物既可以作为分析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。