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: 9309303
• 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/9309303
• 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; Hemoglobin; Hemoglobin concentration result; Human; IgG1; In Vitro; Individual; Iron; 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; Phase III Clinical Trials; Phenotype; Phosphorylation; Production; Protein Engineering; Reporter; Resistance; Role; Series; Signal Transduction; Testing; Therapeutic; TimeLine; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Organisms; Treatment Efficacy; United States; Wild Type Mouse; Work; activin B; beta Thalassemia; bone; bone mass; cell type; clinical application; erythroid differentiation; healthy volunteer; improved; insight; macrophage; member; novel; 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异常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）是一种常见的贫血症。 这是美国面临的一个重大临床挑战，因为许多患者需要长期、昂贵的治疗 为了生存目前，两种新的非常相似的药物，Sotatercept（ACE-011）和Luspatercept（ACE-536）， 正在临床试验中进行测试，并且它们已经在改善BT的贫血和骨量方面取得了成功， 延缓MDS的发病。重要的是，Sotatercept和Luspatercept含有 激活素受体2A（ACVR 2A）和2B（ACVR 2B），并且它们使用非促红细胞生成素（EPO）- 依赖性途径，以增强红细胞（RBC）的生产。他们提出的作用机制是 转化生长因子（TGF）β-样配体，从而通过改变TGF β-样配体的修饰来调节激活素信号传导。 细胞内SMAD复合物。在BT小鼠中的研究表明，这些药物的靶点是TGFβ样 配体生长分化因子11（GDF 11）。此外，已经提出GDF 11在哺乳动物中上调， BT和MDS小鼠的红系细胞，通过SMAD复合物抑制晚期红系分化 磷酸化然而，这些结果与我们的初步数据不一致，这些数据表明Gdf 11 缺失不能重现在用RAP-536处理的动物（小鼠对应物）中观察到的表型 的Luspatercept）。此外，Gdf 11缺失的小鼠继续对RAP-536产生反应。因此，我们假设， GDF 11不是在RAP-536处理的BT小鼠中观察到的改善的唯一靶点， 缺乏GDF 11是增加RBC产量所必需的，但不是充分的。值得注意的是，这些药物也会增加 正常个体和小鼠的红细胞生成。在这里，我们建议调查参与正常的途径， 和无效的红细胞生成，分别使用野生型（WT）和BT小鼠，具体目的如下 (SA)：1。表征RAP-536增加WT小鼠中红细胞生成的机制， 改善BT小鼠的贫血。我们将表征RAP-536处理的WT和BT小鼠中的红细胞生成， 如果这种药物能促进巨噬细胞和成红细胞的相互作用2.调查的后果 同时抑制负责增加红细胞生成的候选配体介导 RAP-536。我们将分别抑制GDF 11、与GDF 11高度同源的GDF 8和激活素B 以及在WT和BT小鼠中的组合，以确定它们的失活是否是增强的 红细胞生成3.确定哪些细胞类型对RAP-536给药有反应， 红系和髓系细胞中的候选Acvr 2A/B受体。我们将使用转基因的SMAD敏感的 报告小鼠，以鉴定哪些细胞在RAP-536处理后显示出改变的途径活性。进一步 在RAP-536处理的BT小鼠中鉴定负责红系表型的细胞，我们将使用 具有Acvr 2A和Acvr 2B的细胞类型特异性缺失的小鼠系。这样的洞察力应该会产生重要的影响。 治疗BT、MDS和其他贫血如炎症性贫血的临床进展。