Pathophysiology and Treatment of Fanconi's Anemia

范可尼贫血的病理生理学和治疗

• 批准号: 8651510
• 负责人: Markus Grompe
• 金额: $ 195.17万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651510
• 关键词: Affect; Androgen Analogues; Aplastic Anemia; Area; BRCA1 gene; BRCA2 gene; BRCA3 gene; Biochemical; Biological Assay; Cell Survival; Cells; Childhood; Chromosome abnormality; Clinical; Congenital Abnormality; Cytogenetics; DNA Repair; Defect; Development; Discipline; Disease; Ensure; Fanconi Anemia-BRCA Pathway; Fanconi anemia protein; Fanconi' s Anemia; Functional disorder; Genes; Genetic; Genome Stability; Goals; Hand; Hematology; Hematopoiesis; Hematopoietic stem cells; Hereditary Disease; Human; Inherited; Intervention; Knockout Mice; Knowledge; Light; Maintenance; Malignant Neoplasms; Marrow; Medical Genetics; Methodology; Modeling; Molecular; Molecular Genetics; Mus; Oncogenes; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Pediatrics; Pharmaceutical Preparations; Phenotype; Pluripotent Stem Cells; Preclinical Drug Evaluation; Predisposition; Process; Proteins; Research Personnel; Role; Stem cells; Syndrome; Technology; Therapeutic; Time; Translating; Ursidae Family; Work; Zebrafish; base; cancer risk; carcinogenesis; clinically relevant; design; developmental genetics; drug discovery; effective intervention; gene discovery; gene repair; gene therapy; induced pluripotent stem cell; insight; interdisciplinary approach; interest; leukemogenesis; malignant breast neoplasm; novel; novel strategies; novel therapeutic intervention; oncology; pre-clinical therapy; programs; screening; small molecule; stem cell biology

Fanconi's Anemia (FA) is a genetic disorder manifesting with typical congenital malformations, childhood onset progressive bone marrow failure and increased cancer risk. 13 genes responsible for FA have been cloned and together constitute the FA/BRCA pathway which functions to maintain genome stability and to ensure stem cell survival. This Program Project will use a multidisciplinary approach to dissecting the molecular pathophysiology of FA and to use this knowledge to enhance therapy for FA, especially small molecule intervention. The clinical disciplines represented by the investigators include pediatrics, medical genetics, hematology and oncology. The scientific areas of expertise include stem cell biology, DNA repair, molecular hematology, zebra fish genetics, mouse genetics, cytogenetics, gene therapy and drug discovery. Core A will use cell-based assays to screen for novel compounds and genes that positively impact the phenotypes of FA cells. New drugs discovered by screening and others derived from insights into pathophysiology will be systematically evaluated in all 3 projects. Project 1 uses zebrafish models of FA, projects 2 and 3 use FA knockout mice as well as pluripotent stem cells from human FA patients. These IPS cells generated by direct reprogramming will be provided by Core C. Cytogenetic abnormalities are a key feature of FA and Core B will provide support in this area. In addition to drug screening the projects will study genetic interactions of the FA/BRCA pathway, work on the non-canonical roles of FA proteins and explore gene repair as a novel approach for gene therapy in the disease.

Fanconi的贫血（FA）是一种遗传疾病，表现出典型的先天性畸形，儿童发作，进行性骨髓衰竭和癌症风险增加。 13负责FA的基因已被克隆，并共同构成FA/BRCA途径，该途径可维持基因组稳定性并确保干细胞存活。 该计划项目将使用多学科方法来剖析FA的分子病理生理学，并使用此知识来增强FA的治疗，尤其是小分子干预。研究人员代表的临床学科包括儿科，医学遗传学，血液学和肿瘤学。专业知识的科学领域包括干细胞生物学，DNA修复，分子血液学，斑马鱼遗传学，小鼠遗传学，细胞遗传学，基因治疗和药物发现。 核心A将使用基于细胞的测定法筛选出对FA细胞表型的积极影响的新型化合物和基因。通过筛查和其他从病理生理学的见解中发现的新药物将在所有3个项目中进行系统评估。项目1使用FA，项目2和3的斑马鱼模型使用FA敲除小鼠以及人类FA患者的多能干细胞。这些通过直接重编程产生的IPS细胞将由CoreC提供。细胞遗传学异常是FA的关键特征，而Core B将在该区域提供支持。除了筛查药物外，项目还将研究FA/BRCA途径的遗传相互作用，从事FA蛋白的非典型作用，并探索基因修复是该疾病基因治疗的一种新方法。