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: 10323011
• 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/10323011
• 关键词: Adult; Aplastic Anemia; Architecture; Blood; Bone marrow failure; 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; 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; translational goal; 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（BMF）包括骨髓增生综合征（MDS），性障碍性贫血（AA）和 阵发性夜间血红蛋白（PNH），是血液产生失败的疾病 细胞衰竭和以体细胞基因组病变的存在为标志的各种克隆性。这些 条件不仅具有日益增长的社会经济和医学重要性，而且他们的基础研究也具有 提供了开创性的发现，对理解生理病理生理的影响有影响 整个血液学领域，造血及以后的机制。我早期的主要重点 作为医师科学家和血液学家的科学职业一直在研究免疫发病机理， 干细胞枚举，干细胞损伤的机制和BMF的分子遗传学。后一个主题 最初包括发现新的体细胞和细菌线病变，然后转变为机械 研究。这些调查线，特别是在R35中特别相关，得出了有关该研究的重要线索 MDS中的突变光谱，后来导致人们对克隆等级和 动态不仅在MD中，而且在AA和PNH中。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金使进步成为可能。我们的经验，承诺 到达田地，并创建的基础设施为持续分子的膨胀提供了坚实的基础 实现新范式转移科学目标的研究。通过利用最新的分子 躯体和细菌线突变的发现以及通过澄清其机械的进展 后果，我们认为现在是时候促进翻译目标来实现切实的进步 医疗服务，包括BMF的诊断和治疗学。这样的调查也将有助于 改善了对通过共同和重要的部分子集介导的基本疾病机制的理解 体细胞突变。我们将使用最新技术，包括单细胞分类和测序，进一步 研究克隆体系结构以识别可靶向的早期事件并确定克隆的依赖性 获得亚克隆病变后这些事件的细胞。这些基因组研究也将涉及 种系病变及其对成年BMF晚期表现的贡献。他们将为基板提供 旨在开发概念上新的治疗策略的机械研究。这个主题最初将 涉及TET2和其他二氧酶，DNMT3A以及其他组蛋白和DNA甲基酶以及剪接体 突变。这些研究还将定义种系改变并使用整合方法的影响 通过存在融合途径来识别疾病亚组，结果将为 合理选择最合适的目标，以制定新的治疗策略。