HRI/elF2aP Signaling Pathway as Potential Pharmaceutical Targets for Thalassemia

HRI/elF2aP 信号通路作为地中海贫血的潜在药物靶点

• 批准号: 8099953
• 负责人: JANE-JANE CHEN
• 金额: $ 0.97万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-30 至 2011-07-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099953
• 关键词: Adverse effects; Affect; Anemia; Apoptosis; Arsenites; Biological Models; Blood Transfusion; Bone Marrow Transplantation; Cells; Chemicals; Clinical; Data; Development; Disease; Embryo; Equilibrium; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Eukaryotic Initiation Factor-2; Fetal Liver; Genes; Globin; Health; Heme; Hemoglobin; Hemoglobinopathies; Hepatocyte; Human; Iron; Iron Chelation; Iron Overload; Iron deficiency anemia; Laboratories; Lead; Life Expectancy; Mediating; Modeling; Molecular; Mus; Mutation; Outcome; Outcome Study; Oxidative Stress; Pain; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Protein Biosynthesis; Protein Dephosphorylation; Protein Kinase; Protein Synthesis Inhibition; Proteins; Quality of life; Reactive Oxygen Species; Recycling; Reporting; Research; Risk; Role; Severities; Signal Pathway; Source; Stress; Symptoms; System; Testing; Thalassemia; Toxic effect; Translational Regulation; World Health; biological adaptation to stress; combat; gene therapy; health economics; heme a; improved; in vivo; inhibitor/antagonist; iron chelation therapy; mouse model; novel; prevent; public health relevance; response; small molecule libraries

DESCRIPTION (provided by applicant): Our long-term objective of this proposed research is to discover novel treatments for red cell disorders with hemoglobinopathy. In this proposal, we focus our efforts on the role of translational regulation in ??thalassemia. Thalassemia is the most common monogenic disease in the world, and is emerging as a major economics and health burden in the world. In addition, it is well established and commonly noticed in ??thalassemic patients that the same mutation in ??globin gene may have drastically different clinical outcome. Hem-regulated eIF21 kinase (HRI) is initially discovered to inhibit general protein synthesis in heme-deficiency of erythroid precursors, and thus balances heme and globin synthesis. Recently, our laboratory has reported that HRI is necessary to reduce the severity not only in iron-deficiency anemia, but also in ??thalassemia. In fact, HRI elicits the most drastic modifier response in mouse models of ??thalassemia to date. HRI mediates this protection by phosphorylation of eIF2?? and inhibition of protein synthesis including ??globin to prevent excessive accumulation of ?-globin aggregates. Thus, HRI and its downstream substrates may be potential pharmaceutical targets for the development of novel treatments of severe thalassemia. The specific aims of this proposal are (1) to test and evaluate the feasibility of salubrinal, a small chemical inhibitor specific for dephosphorylation of eIF2?P, in reducing globin aggregation and apoptosis in Hbb-/- ??thalassemic erythroid precursors; and (2) to screen chemical libraries for compounds that modulate HRI stress response pathway and reduce apoptosis of ??thalassemic erythroid precursors. We will use our compounded mice with deficiencies in HRI and ??major globin genes as a model of a severe form of ??thalassemia. We will examine whether salubrinal can increase eIF2??P level, decrease ?-globin synthesis and aggregation, and reducing proliferation and apoptosis in mouse thalassemic red cell precursors. We will use arsenite induced cell toxicity as a model system for ??thalassemia to screen for chemicals that will protect the survival of erythroid precursors. The molecular mechanisms by which candidate compounds achieve the protection in ?? thalassemic erythroid will be investigated. The outcome of these studies may leads to discovery of novel compounds for treatments of not only thalassemia but also red cell disorders generally. PUBLIC HEALTH RELEVANCE: The purpose of this proposed research is to further our understanding of the pathology of anemia caused by mutations in hemoglobin. This study may also lead to the discovery of novel drug treatments for red blood cell diseases.

描述（由申请人提供）：我们这项拟议研究的长期目标是发现红细胞疾病伴血红蛋白病的新疗法。在这个建议中，我们把我们的努力集中在翻译调控的作用？？地中海贫血地中海贫血是世界上最常见的单基因疾病，并且正在成为世界上主要的经济和健康负担。此外，它是公认的，并普遍注意到在？？地中海贫血患者的基因突变珠蛋白基因可能具有显著不同的临床结果。血红素调节的eIF 21激酶（HRI）最初被发现在血红素缺乏的红系前体中抑制一般蛋白质合成，从而平衡血红素和球蛋白合成。最近，我们的实验室报告说，HRI是必要的，以减少严重程度不仅在缺铁性贫血，但也？地中海贫血事实上，HRI激发了小鼠模型中最激烈的修饰反应？地中海贫血至今。HRI通过磷酸化eIF 2？？和蛋白质合成的抑制，包括？珠蛋白，以防止过度积累？-珠蛋白聚集体。因此，HRI及其下游底物可能是开发重型地中海贫血新治疗方法的潜在药物靶点。本提案的具体目的是（1）测试和评估salubrinal，一个小的化学抑制剂的eIF 2去磷酸化的具体可行性？P，在减少Hbb-/-？地中海贫血性红细胞前体;（2）筛选能调节HRI应激反应途径和减少细胞凋亡的化合物。地中海贫血红细胞前体我们将使用我们的复合小鼠与缺陷的HRI和？主要的珠蛋白基因作为一种严重形式的模型？地中海贫血我们将研究salubrinal是否可以增加eIF 2？P水平，下降？球蛋白合成和聚集，并减少小鼠地中海贫血红细胞前体的增殖和凋亡。我们将使用亚砷酸盐诱导的细胞毒性作为模型系统？地中海贫血筛查保护红细胞前体存活的化学物质。候选化合物实现保护的分子机制？将研究地中海贫血红细胞。这些研究的结果可能会导致发现新的化合物，不仅用于地中海贫血的治疗，而且还用于红细胞疾病的治疗。公共卫生相关性：这项研究的目的是进一步了解血红蛋白突变引起的贫血的病理学。这项研究也可能导致发现新的药物治疗红细胞疾病。