Molecular targeting of erythroid progenitor cells in normal and disordered human erythropoiesis

正常和紊乱的人类红细胞生成中红系祖细胞的分子靶向

• 批准号: 10338073
• 负责人: Lionel Blanc
• 金额: $ 45.08万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338073
• 关键词: Adrenal Cortex Hormones; Adult; Affect; Anemia; BFU-E; Biochemical; Biological; Blood Transfusion; Bone Marrow; CD34 gene; CDKN1C gene; CFU-E; Candidate Disease Gene; Cell Cycle; Cell Cycle Regulation; Cell Nucleus; Cells; Clinical; Clinical Management; Combined Modality Therapy; Data; Defect; Dexamethasone; Diamond-Blackfan anemia; Disease; Disease Management; Dose-Limiting; Drug usage; Dysmyelopoietic Syndromes; Enhancers; Erythroblasts; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; FDA approved; Failure; Fetal Hemoglobin; G1 Phase; Genetic; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Hematological Disease; Hematology; Hematopoietic Stem Cell Transplantation; Human; Immunomodulators; In Vitro; Inherited; Lead; Literature; Maintenance; Measures; Molecular; Molecular Mechanisms of Action; Molecular Target; Morbidity - disease rate; Multiple Myeloma; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Population; Production; Protein Isoforms; Publishing; Regulation; Reporting; Research; Reticulocyte count; Signal Pathway; Signal Transduction; Source; Steroids; TGF Beta Signaling Pathway; Testing; Toxic effect; Transforming Growth Factor beta; Umbilical Cord Blood; base; bone marrow failure syndrome; chromosome 5q loss; cytokine; human model; improved; in vitro Model; lenalidomide; mortality; mouse model; novel drug class; pomalidomide; progenitor; response; stem cells

Project Summary/Abstract Defects in erythropoiesis can ultimately lead to anemia, a major cause of morbidity and mortality worldwide. Diamond Blackfan anemia (DBA), an inherited bone marrow failure syndrome, is an example of disordered erythropoiesis and is currently only curable with hematopoietic stem cell transplantation. With the exception of cytokines, the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide (Pom) and corticosteroids such as dexamethasone (Dex) are the primary pharmacologic agents that directly improve red cell production in patients with erythropoietic defects. Nevertheless, the molecular basis for their effects on erythroid progenitors and precursors is not fully understood. In addition, not all patients with DBA respond to Dex, and only 40% of these have a sustained response without dose-limiting toxicity. The primary research focus of the present proposal is to develop comprehensive mechanistic understanding of effects of Pom and GC on the erythroid progenitors, BFU-E and CFU-E, during human erythropoiesis with the overarching goal to potentially combine them and treat the anemia seen in DBA and other diseases to reduce GC dose-limiting toxicity in patients. Our preliminary data reveal that Pom upregulates TEAD2 and silences the TGF-b at the BFU-E stage. In addition, Dex acts at the CFU-E stage in models of human erythropoiesis. Finally, unlike CFU-E derived from and adult source of CD34+ cells, CFU-E derived from cord blood are unresponsive to Dex. We hypothesize that silencing of TGF-b pathway by Pom will maximize the effects of Dex, thereby limiting the dose needed to treat patients, and its toxicity. Here we propose to investigate the molecular targeting of erythroid progenitors by Pom and Dex in human models of normal and disordered erythropoiesis as proof of concept for the treatment of anemia. Specifically, we will (1) determine the mechanism of action of Pom in human BFU-Es, (2) investigate the mechanism of action of Dex in human CFU-Es through the dynamics of the glucocorticoid receptor and global regulation of the cell cycle, and (3) evaluate whether the combination of Pom and Dex stimulates erythropoiesis in normal progenitor cells and progenitor cells from patients with DBA. These studies will highlight the molecular mechanisms of action of Pom and Dex during human erythropoiesis and further our understanding of normal and disordered red cell production and the appropriate use of these drugs in improved clinical management of bone marrow failure syndromes. Given that these drugs are already FDA-approved for a variety of hematological diseases, we further anticipate their combined use may result in improved clinical managements of disorders with defective red cell production such as DBA.

项目摘要/摘要 红细胞生成的缺陷最终会导致贫血，贫血是发病率和死亡率的主要原因 全世界。遗传性的骨髓衰竭综合征钻石黑凡贫血（DBA）是一个例子 红细胞生成无序，目前只能在造血干细胞移植中治愈。 除细胞因子外，免疫调节药物（IMIDS）Lenalidomide和Pomalidomide （POM）和皮质类固醇（例如地塞米松（Dex））是直接的主要药理剂 改善红细胞生成缺陷患者的红细胞生产。然而，它们的分子基础 对红细胞祖细胞和前体的影响尚不完全了解。另外，并非所有患有DBA的患者 对DEX做出反应，其中只有40％具有持续的反应，而无需限制剂量的毒性。 本提案的主要研究重点是开发全面的机理 了解POM和GC对人类bfu-e和CFU-E的影响的影响 红细胞生成的总体目标是将它们结合起来并治疗DBA中看到的贫血 其他疾病可降低患者的GC剂量限制毒性。我们的初步数据表明POM 在BFU-E阶段上调Tead2并使TGF-B沉默。此外，dex在CFU-E阶段起作用 人类红细胞生成的模型。最后，与CD34+细胞的成人源和成人来源不同，CFU-E，CFU-E 源自脐带血的对DEX无反应。 我们假设POM对TGF-B途径的沉默将最大化DEX的影响，从而 限制治疗患者及其毒性所需的剂量。在这里，我们建议研究分子 POM和DEX在正常和无序的红细胞生成的人类模型中靶向红细胞祖细胞 作为治疗贫血的概念证明。具体而言，我们将（1）确定 人类BFU-ES中的POM，（2）研究DEX在人CFU-ES中的作用机理 糖皮质激素受体的动力学和细胞周期的全局调节，（3）评估是否是否评估 POM和DEX的组合刺激正常祖细胞和祖细胞中的红细胞生成。 DBA患者。 这些研究将突出人类在人类过程中POM和DEX的作用的分子机制 红细胞生成，进一步我们对正常和无序的红细胞生产的理解以及适当的 这些药物在改善骨髓衰竭综合征的临床管理中使用。鉴于这些药物 我们已经被FDA批准为各种血液学疾病，我们进一步预期它们的综合用途 可能会导致红细胞产生缺陷（例如DBA）的疾病的临床管理改善。