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.

正常和无序的红细胞生成激活素信号传导 抽象的 与贫血相关的疾病，例如β-thal症（BT）和骨髓增生综合征（MDS）是A 美国的主要临床挑战，因为许多患者需要慢性，昂贵的治疗 生存。目前是两种小说，非常相似的药物，Sotatercept（ACE-011）和Luspatercept（ACE-536） 在临床试验中进行了测试，它们在改善BT的贫血和骨骼质量方面表现出成功，以及 MDS中疾病发作的延迟。重要的是，Sotatercept和Luspatercept包含 激活素受体2a（ACVR2A）和2B（ACVR2B），它们使用非六粒蛋白（EPO） - 增强红细胞（RBC）产生的依赖途径。他们提出的作用机制是陷阱 转化生长因子（TGF）β样配体，从而通过改变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，这些药物的靶标是TGFβ样 配体生长分化因子11（GDF11）。此外，已经提出了GDF11已更新 BT和MDS小鼠的红细胞细胞，通过SMAD复合物抑制晚期红细胞分化 磷酸化。但是，这些结果与我们的初步数据不一致 缺失未能概括用RAP-536处理的动物观察到的表型（小鼠对应物 Luspatercept）。此外，GDF11骨骼的小鼠继续对RAP536做出反应。那我们假设 GDF11并不是负责RAP-536处理的BT小鼠中观察到的改进的唯一目标 需要缺乏GDF11，但不足以增加RBC的生产。值得注意的是，这些药物也增加了 正常个体和小鼠的红细胞生成。在这里，我们建议研究正常的途径 分别使用野生型（WT）和BT小鼠的无效性红细胞生成，并具有以下特定目的 （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。我们将在RAP-536，WT和BT小鼠中的RAP536中描述红细胞生成，以及 如果该药物促进巨噬细胞 - 金蛋白细胞相互作用。 2。调查后果 简单抑制候选配体负责增加红细胞生成的配体 由RAP-536。我们将抑制与GDF11高度同源的GDF11，GDF8和Activin-B单独 并组合WT和BT小鼠，以确定它们是否需要增强的灭活 红细胞生成。 3。确定哪些细胞类型对RAP-536给药响应 候选红细胞和髓样细胞中的ACVR2A/B受体。我们将使用转基因，Smad响应性， 记者小鼠在RAP-536治疗后识别哪些细胞显示出改变的途径活性。进一步 识别负责RAP-536处理的BT小鼠中负责红系表型的细胞，我们将使用 小鼠系具有ACVR2A和ACVR2B的细胞类型缺失。这种见解应该导致重要 治疗BT，MD和其他贫血的临床进展，例如炎症贫血。