HRI/elF2aP Signaling Pathway as Potential Pharmaceutical Targets for Thalassemia

项目摘要 我们这项拟议研究的长期目标是发现治疗红细胞疾病的新方法 血红蛋白病。在这项提案中，我们将重点放在翻译调节在地中海贫血中的作用上。 地中海贫血是世界上最常见的单基因疾病，并正在成为一种主要的经济和 世界上的健康负担。此外，这一现象在地中海综合征患者中也很常见。 同样的珠蛋白基因突变可能会导致截然不同的临床结果。受HIM监管的eIF2？ 激酶(HRI)最初被发现可抑制红系血色素缺乏症患者的全身蛋白质合成 前体，从而平衡血红素和珠蛋白的合成。最近，我们实验室报告了HRI是 不仅是为了减轻缺铁性贫血的严重程度，也是为了减轻地中海贫血的严重程度。事实上，HRI 在β-地中海贫血小鼠模型中引起迄今为止最剧烈的修饰反应。HRI协调了这一点 EIF2的磷酸化保护作用？和抑制蛋白质合成，包括？-珠蛋白，以防止 ？ -珠蛋白聚集体过度堆积。因此，HRI及其下游底物可能是有潜力的 ？ 开发治疗重型地中海贫血新疗法的药物靶点。的具体目标 这项建议是(1)测试和评价萨鲁布林的可行性，萨鲁布林是一种专用于治疗癌症的小型化学抑制剂 去磷酸化eIF2？p在减少Hbb-/-地中海贫血红系珠蛋白聚集和细胞凋亡中的作用 前体；以及(2)筛选调节HRI应激反应途径的化合物的化学库 减少β-地中海贫血红系前体细胞的凋亡。我们将用我们的复合小鼠 作为一种严重的地中海贫血模型的HRI和主要珠蛋白基因的缺失。我们将研究 沙鲁布林是否能提高eIF2？p水平，降低？-珠蛋白合成和聚集，并降低 小鼠地中海贫血红细胞前体细胞的增殖和凋亡。我们将使用亚砷酸盐诱导的细胞毒性 作为地中海贫血的模型系统来筛选保护红系存活的化学物质 先驱物。候选化合物实现保护的分子机制是什么？ 将对地中海贫血红系进行研究，这些研究的结果可能会导致新的发现 不仅用于治疗地中海贫血，而且通常也用于治疗红细胞疾病的化合物。项目叙事 这项拟议研究的目的是加深我们对由以下原因引起的贫血的病理学的了解 血红蛋白的突变。这项研究还可能导致发现治疗红细胞的新药物。 疾病。

Project Summary 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 ??thalssemia. 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 ??thalssemic patients that the same mutation in ??globin gene may have drastically different clinical outcome. Hem-regulated eIF2? 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 tocixity 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. Project Narrative 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.