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: 10534759
• 负责人: Lionel Blanc
• 金额: $ 44.87万
• 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/10534759
• 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; In Vitro; Inherited; Literature; Maintenance; Measures; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Target; Morbidity - disease rate; Multiple Myeloma; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Population; Production; Proliferating; 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; bone marrow failure syndrome; candidate validation; chromosome 5q loss; cytokine; data integration; human model; immune modulating agents; improved; in vitro Model; lenalidomide; mortality; mouse model; novel drug class; pharmacologic; 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 红细胞生成缺陷最终会导致贫血，贫血是发病和死亡的主要原因。 全世界。钻石黑粉贫血(DBA)是一种遗传性骨髓衰竭综合征，是 红血球生成障碍，目前只能通过造血干细胞移植治愈。 除细胞因子外，免疫调节药物(IMids)为来那度胺和泊马度胺 (POM)和皮质类固醇，如地塞米松(Dex)是直接 改善红细胞生成缺陷患者的红细胞生成。然而，它们的分子基础 对红系祖细胞和红系祖细胞的影响尚不完全清楚。此外，并非所有DBA患者 对地塞米松有反应，其中只有40%有持续反应，没有剂量限制毒性。 本方案的主要研究重点是发展综合机械化 POM和GC对人红系祖细胞BFU-E和CFU-E影响的研究 红细胞生成的首要目标是潜在地将它们结合起来，并治疗DBA和 其他疾病可降低GC对患者的剂量限制毒性。我们的初步数据显示，POM 在BFU-E阶段，上调TEAD2并沉默转化生长因子-β。此外，Dex还在#年CFU-E阶段扮演角色 人类红细胞生成的模型。最后，与来源于CD34+细胞和成人来源的CFU-E不同，CFU-E 从脐带血中提取的药物对地塞米松没有反应。 我们假设POM沉默转化生长因子-b通路将使Dex的作用最大化，从而 限制治疗患者所需的剂量及其毒性。在这里，我们建议研究分子 POM和Dex在人正常和异常红细胞生成模型中对红系祖细胞的靶向作用 作为治疗贫血的概念证明。具体地说，我们将(1)确定 (2)探讨地塞米松在人CFU-ES中的作用机制。 糖皮质激素受体的动力学和细胞周期的全局调节，以及(3)评估 多酚和地塞米松联合用药对正常祖细胞和正常骨髓祖细胞的促红细胞生成作用 DBA患者。 这些研究将突出多酚和地塞米松在人体内的分子作用机制。 红细胞生成和加深我们对正常和无序的红细胞产生的理解以及适当的 这些药物在改善骨髓衰竭综合征的临床管理中的使用。鉴于这些药物 已经被FDA批准用于各种血液疾病，我们进一步预计它们将联合使用 可能导致改善对红细胞产生缺陷的疾病的临床管理，如DBA。

项目成果

Synthesis and pharmacological evaluation of pomalidomide derivatives useful for sickle cell disease treatment.

• DOI: 10.1016/j.bioorg.2021.105077
• 发表时间: 2021-09
• 期刊: Bioorganic chemistry
• 影响因子: 5.1
• 作者: de Melo TRF;Dulmovits BM;Fernandes GFDS;de Souza CM;Lanaro C;He M;Al Abed Y;Chung MC;Blanc L;Costa FF;Dos Santos JL
• 通讯作者: Dos Santos JL

Targeting of Calbindin 1 rescues erythropoiesis in a human model of Diamond Blackfan anemia.

靶向 Calbindin 1 可挽救 Diamond Blackfan 贫血人类模型中的红细胞生成。

• DOI: 10.1016/j.bcmd.2023.102759
• 发表时间: 2023
• 期刊: Blood cells, molecules & diseases
• 作者: Wang,Nan;LaVasseur,Corinne;Riaz,Rao;Papoin,Julien;Blanc,Lionel;Narla,Anupama
• 通讯作者: Narla,Anupama