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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要红细胞生成缺陷最终会导致贫血，这是发病和死亡的主要原因全世界。戴蒙德·布莱克范贫血 (DBA) 是一种遗传性骨髓衰竭综合征，是红细胞生成紊乱，目前只能通过造血干细胞移植来治愈。除细胞因子外，免疫调节药物 (IMiD) 来那度胺和泊马度胺 (Pom) 和皮质类固醇如地塞米松 (Dex) 是直接作用的主要药物改善红细胞生成缺陷患者的红细胞生成。尽管如此，它们的分子基础对红系祖细胞和前体细胞的影响尚未完全了解。此外，并非所有 DBA 患者对 Dex 有反应，其中只有 40% 具有持续反应且没有剂量限制性毒性。本提案的主要研究重点是开发综合机制了解 Pom 和 GC 对人类红系祖细胞 BFU-E 和 CFU-E 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 和减少其他疾病患者的GC剂量限制性毒性。我们的初步数据表明，Pom 在 BFU-E 阶段上调 TEAD2 并沉默 TGF-b。此外，Dex 在 CFU-E 阶段发挥作用人类红细胞生成模型。最后，与源自 CD34+ 细胞和成人来源的 CFU-E 不同，CFU-E 源自脐带血的细胞对 Dex 没有反应。我们假设 Pom 沉默 TGF-b 通路将最大限度地发挥 Dex 的作用，从而限制治疗患者所需的剂量及其毒性。在这里，我们建议研究分子在正常和紊乱红细胞生成的人类模型中，Pom 和 Dex 靶向红系祖细胞作为治疗贫血的概念证明。具体来说，我们将（1）确定作用机制人 BFU-E 中的 Pom，(2) 通过糖皮质激素受体的动态和细胞周期的整体调节，以及（3）评估是否 Pom 和 Dex 的组合刺激正常祖细胞和来自 DBA患者。这些研究将强调 Pom 和 Dex 在人体过程中作用的分子机制。红细胞生成，进一步了解正常和紊乱的红细胞生成以及适当的红细胞生成使用这些药物可改善骨髓衰竭综合征的临床管理。鉴于这些药物已获得 FDA 批准用于多种血液疾病，我们进一步预计它们的联合使用可能会改善红细胞生成缺陷性疾病（如 DBA）的临床管理。