Translational Studies of Inherited Marrow Failure and Myelodysplastic Syndromes

遗传性骨髓衰竭和骨髓增生异常综合征的转化研究

• 批准号: 9144794
• 负责人: Janis L Abkowitz
• 金额: $ 163.61万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-29 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144794
• 关键词: Address; Adult; Advanced Development; Algorithms; Biological; Biological Markers; Blood Cells; Bone Marrow; Boston; Categories; Child; Childhood; Clinic; Clinical; Clinical Data; Clinical Research; Collaborations; Communities; Country; Custom; DNA; DNA Sequence Alteration; Data Collection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Dysmyelopoietic Syndromes; Essential Genes; Failure; Future; General Population; Genes; Genetic; Genomic approach; Genomics; Germ-Line Mutation; Goals; Grant; Health; Hematologist; Hematology; Hematopathology; Hematopoiesis; Inborn Genetic Diseases; Incidence; Inherited; Investigation; Knowledge; Marrow; Medical; Methodology; Methods; Molecular; Molecular Genetics; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Pancytopenia; Pathogenesis; Pathologic; Pathologist; Pathology; Pathway interactions; Patients; Phenotype; Population; Production; Recording of previous events; Research; Research Personnel; Resource Development; Resources; Role; Sampling; Somatic Mutation; Syndrome; Technology; Testing; Variant; accurate diagnosis; base; clinical phenotype; cytopenia; evidence base; exome; falls; gene discovery; imaging modality; insight; leukemia; member; molecular phenotype; multidisciplinary; next generation sequencing; novel; novel diagnostics; outcome forecast; programs; repository; screening; tool; translational study; working group; young adult

DESCRIPTION (provided by applicant): The inherited bone marrow failure and myelodysplastic syndromes (iBMF/MDS) are a heterogeneous group of disorders that are characterized by impaired hematopoiesis and a propensity to progress to leukemia. Despite recent advances in the field, a significant percentage of patients presenting with inherited marrow failure or MDS do not fall into the known diagnostic categories and remain idiopathic. Since many of these genetic syndromes entail specific management and treatment considerations that differ significantly from standard therapies used for acquired marrow failure/MDS, accurate diagnosis is essential. This is a resource development and gene discovery grant investigating iBMF/MDS to characterize their phenotypic spectrum, to develop novel imaging modalities for bone marrow pathology, and to gain insights into the genetic and molecular mechanisms regulating hematopoiesis and marrow failure. We will apply cutting edge genomics approaches to samples from comprehensively phenotyped children and adults to identify new genes responsible for iBMF/MDS. This project will also investigate the clinical and biological consequences of somatically acquired genetic mutations on disease progression and prognosis in iBMF/MDS and determine the similarities or differences in genetic landscapes between inherited versus acquired marrow failure/MDS. We will also interrogate seemingly sporadic marrow failure or MDS presenting in the general population for cryptic presentations of inherited disorders. Resources generated for the broader clinical and scientific communities will include high-throughput multiplexed gene analysis platforms for iBMF/MDS, evidence- based algorithms for the diagnostic workup and management of iBMF/MDS, centralized hematopathology review, and comprehensively clinically annotated biological samples for further investigation. This project should yield new insights into blood cell development and the molecular pathogenesis of marrow failure and MDS; will advance the development of new diagnostic tests, therapies and biomarkers for marrow failure and MDS; will provide clinical resources forthe hematology community; and will provide new tools and methods for future studies ofthe molecular pathways regulating hematopoiesis.

描述（由申请人提供）：遗传性骨髓衰竭和骨髓增生异常综合征（iBMF/MDS）是一组异质性疾病，其特征是造血受损和有进展为白血病的倾向。尽管该领域最近取得了进展，但仍有相当大比例的患有遗传性骨髓衰竭或骨髓增生异常综合征的患者不属于已知的诊断类别，并且仍然是特发性的。由于许多遗传综合征需要特定的管理和治疗注意事项，与用于获得性骨髓衰竭/M​​DS 的标准疗法显着不同，因此准确的诊断至关重要。这是一项资源开发和基因发现赠款，旨在研究 iBMF/MDS，以表征其表型谱，开发骨髓病理学的新型成像模式，并深入了解调节造血和骨髓衰竭的遗传和分子机制。我们将对来自全面表型的儿童和成人的样本应用最先进的基因组学方法，以确定导致 iBMF/MDS 的新基因。该项目还将研究体细胞获得性基因突变对 iBMF/MDS 疾病进展和预后的临床和生物学影响，并确定遗传性骨髓衰竭/M​​DS 与获得性骨髓衰竭/M​​DS 之间遗传景观的相似性或差异。我们还将询问普通人群中看似散发的骨髓衰竭或骨髓增生异常综合征（MDS）是否是遗传性疾病的隐秘表现。为更广泛的临床和科学界产生的资源将包括 iBMF/MDS 的高通量多重基因分析平台、用于 iBMF/MDS 诊断检查和管理的循证算法、集中血液病理学审查以及全面临床注释的生物样本，以供进一步研究。调查。该项目将为血细胞发育以及骨髓衰竭和骨髓增生异常综合征的分子发病机制带来新的见解；将推动针对骨髓衰竭和MDS的新诊断测试、疗法和生物标志物的开发；将为血液学界提供临床资源；将为今后研究调控造血的分子途径提供新的工具和方法。