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

基本信息

批准号：
10216113
负责人：
STEFANO RIVELLA
金额：
$ 8.35万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
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/10216113
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

项目摘要

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.

正常和紊乱红细胞生成中的激活素信号传导抽象的与贫血相关的疾病，如 β 地中海贫血 (BT) 和骨髓增生异常综合征 (MDS) 是一种这是美国面临的主要临床挑战，因为其中许多患者需要长期、昂贵的治疗目前有两种非常相似的新型药物 Sotatercept (ACE-011) 和 Luspatercept (ACE-536)。正在临床试验中进行测试，并且在 BT 中显示出在改善贫血和骨量方面取得了成功，并且重要的是，Sotatercept 和 Luspatercept 含有细胞外结构域。激活素受体 2A (ACVR2A) 和 2B (ACVR2B) 分别，并且它们使用非促红细胞生成素 (EPO)- 他们提出的作用机制是捕获。转化生长因子 (TGF) β 样配体，从而通过改变修饰来调节激活素信号传导对 BT 小鼠的细胞内 SMAD 复合物的研究表明，这些药物的靶标是 TGFβ 样物质。配体生长分化因子 11 (GDF11) 此外，有人提出 GDF11 在细胞中表达上调。 BT 和 MDS 小鼠的红细胞，通过 SMAD 复合物抑制晚期红细胞分化然而，这些结果与我们显示 Gdf11 的初步数据不一致。删除未能重现在用 RAP-536 治疗的动物（小鼠对应物）中观察到的表型 Luspatercept 的）此外，Gdf11 缺失的小鼠继续对 RAP-536 做出反应。 GDF11 并不是 RAP-536 治疗的 BT 小鼠中观察到的改善的唯一靶标，或者缺乏 GDF11 是增加红细胞生成所必需的，但还不够。值得注意的是，这些药物也会增加红细胞生成。在这里，我们建议研究正常个体和小鼠的红细胞生成过程。分别使用野生型 (WT) 和 BT 小鼠进行无效红细胞生成，具有以下具体目标 (SA): 1. 描述 RAP-536 增加 WT 小鼠红细胞生成的机制改善 BT 小鼠的贫血症我们将描述 RAP-536 治疗的 WT 和 BT 小鼠的红细胞生成情况。如果该药物促进巨噬细胞-成红细胞相互作用 2. 研究其后果。同时抑制负责介导红细胞生成增加的候选配体我们将分别抑制 GDF11、GDF8（与 GDF11 高度同源）和 Activin-B。并在 WT 和 BT 小鼠中组合，以确定它们的失活是否对于增强 3. 通过针对 RAP-536 给药来确定哪些细胞类型有反应。红细胞和骨髓细胞中的候选 Acvr2A/B 受体我们将使用转基因、SMAD 反应性、报告小鼠以确定哪些细胞在 RAP-536 治疗后表现出改变的通路活性。为了识别 RAP-536 治疗的 BT 小鼠中负责红细胞表型的细胞，我们将使用具有细胞类型特异性 Acvr2A 和 Acvr2B 缺失的小鼠品系应该会带来重要的结果。治疗 BT、MDS 和其他贫血（例如炎症性贫血）的临床进展。