Therapeutic Implications of Molecular Defects in Bone Marrow Failure

骨髓衰竭中分子缺陷的治疗意义

• 批准号: 10080100
• 负责人: Jaroslaw P Maciejewski
• 金额: $ 95.1万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-12 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080100
• 关键词: Adult; Aplastic Anemia; Architecture; Blood; Caring; Cell Separation; Clonality; Clone Cells; DNA; Defect; Dependence; Development; Diagnostic; Dioxygenases; Disease; Dysmyelopoietic Syndromes; Event; Failure; Funding; Genetic Diseases; Genomics; Germ Lines; Germ-Line Mutation; Goals; Hematologist; Hematology; Hematopoiesis; Histones; Immune; Infrastructure; Investigation; Lesion; Mediating; Medical; Methyltransferase; Molecular; Molecular Genetics; Mutation; National Heart, Lung, and Blood Institute; Pancytopenia; Pathogenesis; Pathway interactions; Physicians; Physiological; Production; Role; Scientist; Solid; Somatic Mutation; Source; Technology; Therapeutic; Time; base; bone marrow failure syndrome; career; cell injury; disorder subtype; experience; improved; novel therapeutic intervention; socioeconomics; stem cells; treatment strategy

ABSTRACT Bone marrow failure syndromes (BMFS) include myelodysplastic syndrome (MDS), aplastic anemia (AA) and paroxysmal nocturnal hemoglobiuria (PNH) and are diseases characterized by failed blood production, stem cell failure and various degrees of clonality marked by the presence of somatic genomic lesions. These conditions have not only a growing socioeconomic and medical importance, but also their basic study has provided ground-breaking discoveries with implications for the understanding the physiologic pathophysiologic mechanisms within hematopoiesis and beyond for the whole field of hematology. The main focus of my early scientific career as physician scientist and hematologist has been on study immune pathogenesis, ways of stem cell enumeration, mechanisms of stem cell damage and molecular genetics of BMFS. The latter themes initially included discovery of new somatic and germ line lesions and subsequently transitioned to mechanistic studies. These lines of investigations, specifically pertinent in this R35, yielded important clues as to the mutational spectrum in MDS and later led to the growing appreciation of the role of clonal hierarchy and dynamics not only in MDS, but also in AA and PNH. Our team has made significant contribution to these advances made possible by a continuous funding from NHLBI and other sources. Our experience, commitment to the field, and created infrastructure provide a solid base for proposed expansions of ongoing molecular studies towards new paradigm-shifting scientific goals. By taking advantage of the newest molecular discoveries of somatic and germ line mutations and through progress in clarifying their mechanistic consequences, we believe that it is now time to advance translational goals to make tangible advances in medical care including diagnostics and therapeutics for BMFS. Such investigations would also contribute to improved understanding of basic disease mechanisms mediated by selected subset of common and important somatic mutations. We will use the newest technologies, including single cell sorting and sequencing, to further study the clonal architecture to identify targetable early events and also determine the dependence of clonal cells on these events following acquisition of subclonal lesions. These genomic investigations will involve also germ line lesions and their contribution of late manifestation of adult BMFs. They will provide substrates for mechanistic studies aiming at development of conceptually new therapeutic strategies. This theme will initially involve TET2 and other dioxygenases, DNMT3A and other histone and DNA methylases and spliceosomal mutations. These studies will also define the impact of germ line alteration and using integrative approaches identify disease subgroups by the presence of convergent pathways and results will provide a canvas for the rational selection of most suitable targets for development of new treatment strategies.

抽象的 骨髓衰竭综合征（BMFS）包括骨髓增生异常综合征（MDS）、再生障碍性贫血（AA）和 阵发性睡眠性血红尿症 (PNH) 是一种以血液生成障碍、干细胞障碍为特征的疾病 以体细胞基因组损伤为标志的细胞衰竭和不同程度的克隆性。这些 条件不仅具有日益增长的社会经济和医学重要性，而且其基础研究也已变得越来越重要。 提供了突破性的发现，对理解生理病理生理学具有重要意义 整个血液学领域的造血及其他机制。我早期的主要关注点 作为医师科学家和血液学家的科学生涯一直致力于研究免疫发病机制、方法 干细胞计数、干细胞损伤机制和 BMFS 分子遗传学。后面的主题 最初包括发现新的体细胞和种系病变，随后转向机械性病变 研究。这些调查，特别是与 R35 相关的调查，提供了关于 MDS 中的突变谱，后来导致人们越来越认识到克隆等级和 动态不仅在 MDS 中存在，而且在 AA 和 PNH 中也存在。我们的团队为这些做出了重大贡献 NHLBI 和其他来源的持续资助使得进展成为可能。我们的经验、承诺 到现场，并创建的基础设施为正在进行的分子生物学的拟议扩展提供了坚实的基础 研究朝着新的范式转变的科学目标。通过利用最新的分子 体细胞和种系突变的发现以及阐明其机制的进展 后果，我们认为现在是时候推进转化目标，以在以下方面取得切实进展： 医疗护理，包括 BMFS 的诊断和治疗。此类调查也将有助于 提高对常见和重要疾病的选定子集介导的基本疾病机制的理解 体细胞突变。我们将使用最新的技术，包括单细胞分选和测序，进一步 研究克隆结构以确定可靶向的早期事件并确定克隆的依赖性 获得亚克隆病变后细胞对这些事件的影响。这些基因组研究还将涉及 种系病变及其对成人 BMF 晚期表现的贡献。他们将为 旨在开发概念性新治疗策略的机制研究。该主题最初将 涉及 TET2 和其他双加氧酶、DNMT3A 和其他组蛋白和 DNA 甲基化酶以及剪接体 突变。这些研究还将定义种系改变和使用综合方法的影响 通过收敛途径的存在来识别疾病亚组，结果将为 合理选择最合适的靶点以制定新的治疗策略。