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.

项目总结/文摘

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