Activin signaling in normal and disordered erythropoiesis

正常和紊乱红细胞生成中的激活素信号传导

• 批准号: 9889103
• 负责人: STEFANO RIVELLA
• 金额: $ 37.8万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889103
• 关键词: Activin Receptor; Activins; Affect; Anemia; Anemia due to Chronic Disorder; Animals; Antibodies; Bone Marrow Cells; CD34 gene; Cell Maturation; Cells; Chronic; Clinical; Clinical Trials; Complement Factor B; Complex; Data; Development; Disease; Drug Targeting; Dysmyelopoietic Syndromes; Engineering; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Extracellular Domain; GDF11 gene; GDF8 gene; Goals; Hematology; Hemoglobin concentration result; Human; IgG1; In Vitro; Individual; Iron Overload; Knock-out; Lead; Ligand Binding; Ligands; MADH2 gene; Mediating; Mediator of activation protein; Modification; Mus; Myeloid Cells; Onset of illness; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I/II Trial; Phenotype; Phosphorylation; Production; Protein Engineering; Reporter; Resistance; Role; Series; Signal Transduction; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Organisms; Treatment Efficacy; United States; Wild Type Mouse; Work; activin B; beta Thalassemia; bone mass; cell type; clinical application; erythroid differentiation; healthy volunteer; improved; insight; iron absorption; macrophage; member; novel; phase III trial; receptor; success; therapeutic target

Activin signaling in normal and disordered erythropoiesis ABSTRACT Disorders associated with anemia such as β-thalassemia (BT) and myelodysplastic syndrome (MDS) are a major clinical challenge in the United States, as many of these patients require chronic, expensive treatment for survival. Two novel, very similar drugs, Sotatercept (ACE-011) and Luspatercept (ACE-536), are presently being tested in clinical trials, and they have shown success in improving anemia and bone mass in BT, and delay of disease onset in MDS. Importantly, Sotatercept and Luspatercept contain the extracellular domain of activin receptor 2A (ACVR2A) and 2B (ACVR2B), respectively, and they use a non-erythropoietin (EPO)- dependent pathway to enhance red blood cell (RBC) production. Their proposed mechanism of action is to trap transforming growth factor (TGF) β-like ligands, thereby modulating activin signaling via altered modification of the intracellular SMAD complex. Studies in BT mice suggest that the target of these drugs is the TGFβ-like ligand growth differentiation factor 11 (GDF11). Moreover, it has been proposed that GDF11 is upregulated in erythroid cells of BT and MDS mice, inhibiting late-stage erythroid differentiation via SMAD complex phosphorylation. However, these results are not consistent with our preliminary data showing that Gdf11 deletion failed to recapitulate the phenotype observed in animals treated with RAP-536 (the mouse counterpart of Luspatercept). In addition, Gdf11-deleted mice continued to respond to RAP-536. Thus, we hypothesize that GDF11 is not the sole target responsible for the improvements observed in RAP-536-treated BT mice or that lack of GDF11 is required, but not sufficient, for increased RBC production. Of note, these drugs also increase erythropoiesis in normal individuals and mice. Here, we propose to investigate the pathways involved in normal and ineffective erythropoiesis using wild-type (WT) and BT mice, respectively, with the following specific aims (SA): 1. Characterize the mechanisms by which RAP-536 increases erythropoiesis in WT mice and improves anemia in BT mice. We will characterize erythropoiesis in RAP-536 treated, WT and BT mice, and if this drug promotes macrophage-erythroblast interaction. 2. Investigate the consequences of simultaneous inhibition of the candidate ligands responsible for the increased erythropoiesis mediated by RAP-536. We will inhibit GDF11, GDF8, which is highly homologous to GDF11, and Activin-B, individually and in combination in WT and BT mice, to determine whether their inactivation is necessary for enhanced erythropoiesis. 3. Identify which cell types respond to RAP-536 administration by targeting the candidate Acvr2A/B receptors in erythroid and myeloid cells. We will use transgenic, SMAD-responsive, reporter mice to identify which cells show altered pathway activity following RAP-536 treatment. To further identify the cells that are responsible for the erythroid phenotype in RAP-536-treated, BT mice, we will use mouse lines with cell-type-specific deletions of Acvr2A and Acvr2B. Such insight should result in important clinical advances in treating BT, MDS, and other anemias, such as anemia of inflammation.

激活素信号在正常和紊乱的红细胞生成中的作用 摘要 与贫血相关的疾病，如β-地中海贫血(BT)和骨髓增生异常综合征(MDS)是一种 美国的主要临床挑战，因为这些患者中的许多人需要长期昂贵的治疗 为了生存。两种非常相似的新药Sotatercept(ACE-011)和Luspatercept(ACE-536)目前正在 在临床试验中进行测试，它们在改善Bt贫血和骨量方面取得了成功，以及 MDS的发病延迟。重要的是，Sotatercept和Luspatercept含有胞外结构域 激活素受体2A(ACVR2A)和激活素受体2B(ACVR2B)，它们使用非促红细胞生成素(EPO)- 增加红细胞(RBC)产生的依赖途径。他们提出的行动机制是诱捕 转化生长因子β样配体，从而通过改变改变的修饰来调节激活素信号 细胞内的SMAD复合体。对Bt小鼠的研究表明，这些药物的靶点是转化生长因子β样蛋白 配体生长分化因子11(GDF11)此外，有人建议将GDF11上调到 Bt和MDS小鼠红系细胞通过SMAD复合体抑制晚期红系分化 磷酸化。然而，这些结果与我们初步数据显示的Gdf11并不一致 缺失未能概括用RAP-536(小鼠对应物)处理的动物的表型 Luspatercept)。此外，Gdf11缺失的小鼠继续对RAP-536有反应。因此，我们假设 GDF11不是RAP-536处理的Bt小鼠观察到的改善或 缺乏GDF11是增加红细胞产量所必需的，但不是充分的。值得注意的是，这些药物也增加了 正常人和小鼠的红细胞生成。在这里，我们建议研究正常所涉及的通路 和分别使用野生型(WT)和Bt小鼠的无效红细胞生成，具体目的如下 (SA)：1.鉴定RAP-536促进WT小鼠和WT小鼠红细胞生成的机制 改善Bt小鼠的贫血。我们将表征RAP-536处理的WT和BT小鼠的红细胞生成情况，以及 如果这种药物促进巨噬细胞和红细胞的相互作用。2.调查以下行为的后果 同时抑制介导的红细胞生成增加的候选配体 由RAP-536提供。我们将分别抑制GDF11、与GDF11高度同源的GDF8和激活素-B 并在WT和BT小鼠中结合使用，以确定它们的失活是否需要增强 红血球生成。3.通过靶向RAP-536药物治疗确定哪些细胞类型对RAP-536治疗有反应 红系和髓系细胞的Acvr2A/B候选受体。我们将使用转基因的、对SMAD有反应的 报告小鼠，以确定哪些细胞在RAP-536处理后显示出改变的途径活性。为了进一步 确定在RAP-536处理的Bt小鼠中导致红系表型的细胞，我们将使用 Acvr2A和Acvr2B细胞类型特异性缺失的小鼠株系。这种洞察力应该会导致重要的 治疗Bt、MDS和其他贫血的临床进展，如炎症性贫血。