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Novel regulators of stress erythropoiesis

应激性红细胞生成的新型调节剂

基本信息

批准号：
9534324
负责人：
DON Michael WOJCHOWSKI
金额：
$ 30.42万
依托单位：
UNIVERSITY OF NEW HAMPSHIRE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9534324
关键词：
Activin Receptor Adverse effects Anemia Autophagocytosis CD34 gene Cathepsins Cathepsins B Cessation of life Chronic Chronic Kidney Failure Chronic stress Coupled Cytoprotection Cytoprotective Agent Dose Dysmyelopoietic Syndromes EPOR gene End stage renal failure Equilibrium Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythroid Progenitor Cells Erythropoiesis Event Glucocorticoids Glycoproteins Health Hemoglobinopathies Hormones Human Hypersensitivity Inflammation Investigation Iron Knockout Mice Link Lysosomes MEKs Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Molecular Mechanisms of Action Multiple Myeloma Mus Oxidative Stress Pathway interactions Patients Peptide Hydrolases Pharmacology Phenocopy Proteins RNA-Binding Proteins Radiation therapy Recombinants Role Serpins Sickle Cell Anemia Stress System Thalassemia Therapeutic Transfusion Translating Work ZFP36L2 gene aged beta Thalassemia biological adaptation to stress cancer radiation therapy cancer therapy carboxypeptidase C chemotherapy cost cytotoxic hydroxyurea inhibitor/antagonist insight mouse model novel progenitor public health relevance response tissue oxygenation

项目摘要

DESCRIPTION (provided by applicant): Anemia as associated with end-stage renal disease, chemo- and radiation therapies, inflammation, myelodysplasia, iron dysregulation and hemoglobinopathies leads to chronic bouts of accelerated, yet stressed and often compromised erythropoiesis. A specific understanding of key regulators of such stress erythropoiesis is of basic importance for insight into new anemia therapies. rhEPO per se can be therapeutic, but has substantial hypertensive side-effects, evokes thrombolytic events, is a high-cost recombinant glycoprotein, and may worsen certain cancers. Via investigations of EPO's effects on primary erythroid progenitors, we have uncovered and initially characterized two important new factors (and associated pathways) that selectively regulate stress erythropoiesis. First, our studies of a novel EPO-induced intracellular Spi2A serpin (via a new KO model) reveal that under select stress conditions, erythroblasts become highly sensitive to lysosome damage to the extent of leaching lysosomal executioner cathepsins- which are inhibited by Spi2A. If unchecked, cathepsin-associated damage and erythroblast death escalate, with ROS and iron as cytotoxic co-factors. We also demonstrate that a Cathepsin B/L inhibitor can phenocopy Spi2A's cytoprotective effects. A second EPO co-induced erythropoietic regulator we have discovered (and are beginning to understand) is the molecular adaptor and pseudokinase, Trib3. By developing a Trib3-KO mouse model, we reveal non-redundant novel stress erythropoiesis specific roles for Trib3 during both early, and late- stage erythroid cell formation We will now advance insight into these two new stress erythropoiesis factors, and coupled pathways, via the following SPECIFIC AIMS: SA#1 will first define how Spi2A and linked pathways impact on stress erythropoiesis due to β-thalassemia and iron imbalance (#1.1). At a mechanistic level, consequences of Spi2A- deficiency on erythroblast autophagy will be determined and molecular damage incurred by erythroblast lysosomes during oxidative stress plus Spi2A-deficiency will be defined (#1.2). Via LOF studies, SA#2 first will define effects exerted by Trib3 pseudokinase on early- and late-stage erythropoiesis during β-thalassemia, and iron imbalance (#2.1). Aim 2.2 will determine Trib3's roles in unfolded protein response pathways together with Trib3's regulatory molecular action mechanisms in early- and late- stage erythroid cells. SA#3 will advance studies to primary human erythroid progenitors (including thalassemia), and will first determine effects of lysosomal compromise, and cathepsin inhibition on erythroblast cytoprotection (#3.1). Aim 3.2 will define effects of Trib3 LOF and GOF during erythropoietic stress. Substantial insight will be gained concerning new regulators of red cell formation and novel target pathways within compromised erythroid progenitors for anti- anemia agents.

描述（由申请人提供）：与终末期肾病、化疗和放疗、炎症、骨髓增生异常、铁调节异常和血红蛋白病相关的贫血导致慢性发作的加速、应激和经常受损的红细胞生成。对这种应激性红细胞生成的关键调节因子的具体理解对于深入了解新的贫血疗法具有基本的重要性。rhEPO本身可以是治疗性的，但具有显著的高血压副作用，引起血栓溶解事件，是高成本的重组糖蛋白，并且可能使某些癌症恶化。通过研究EPO对初级红系祖细胞的影响，我们发现并初步表征了两个重要的新因子（和相关途径），它们选择性地调节应激红细胞生成。首先，我们对一种新的EPO诱导的细胞内Spi 2A丝氨酸蛋白酶抑制剂的研究（通过一种新的KO模型）表明，在选择的应激条件下，成红细胞对溶酶体损伤变得高度敏感，达到浸出溶酶体执行者组织蛋白酶的程度-这被Spi 2A抑制。如果不加抑制，组织蛋白酶相关的损伤和成红细胞死亡会升级，ROS和铁作为细胞毒性辅助因子。我们还证明了组织蛋白酶B/L抑制剂可以表型复制Spi 2A的细胞保护作用。我们发现的第二个EPO共诱导的红细胞生成调节因子（并开始了解）是分子适配器和假激酶Trib 3。通过开发Trib 3-KO小鼠模型，我们揭示了Trib 3在早期和晚期红系细胞形成期间的非冗余的新型应激红细胞生成特异性作用。我们现在将通过以下具体目标推进对这两种新的应激红细胞生成因子和偶联途径的了解：SA#1将首先定义Spi 2A和相关通路如何影响β-地中海贫血和铁失衡引起的应激性红细胞生成（#1.1）。在机制水平上，将确定Spi 2A缺乏对成红细胞自噬的后果，并定义在氧化应激加Spi 2A缺乏期间成红细胞溶酶体引起的分子损伤（#1.2）。通过LOF研究，SA#2首先将确定Trib 3假激酶对β-地中海贫血和铁失衡期间早期和晚期红细胞生成的影响（#2.1）。目的2.2将确定Trib 3在未折叠蛋白反应途径中的作用以及Trib 3在早期和晚期红系细胞中的调节分子作用机制。SA#3将推进对原代人红系祖细胞（包括地中海贫血）的研究，并将首先确定溶酶体损害和组织蛋白酶抑制对成红细胞细胞保护的影响（#3.1）。目的3.2将定义Trib 3 LOF和GOF在红细胞生成应激期间的作用。将获得关于红细胞形成的新调节剂和抗贫血剂的受损红系祖细胞内的新靶向途径的实质性见解。