HRI/elF2aP Signaling Pathway as Potential Pharmaceutical Targets for Thalassemia

描述（由申请人提供）：我们提出的这项研究的长期目标是发现血红蛋白病红细胞疾病的新治疗方法。在本论文中，我们将重点研究翻译调控在地中海贫血中的作用。地中海贫血是世界上最常见的单基因疾病，正在成为世界上一个主要的经济和卫生负担。此外，它在？？地中海贫血患者身上有相同的突变？？珠蛋白基因可能有截然不同的临床结果。血红素调节的eIF21激酶（HRI）最初被发现可以抑制红系前体血红素缺乏时的一般蛋白质合成，从而平衡血红素和球蛋白的合成。最近，我们的实验室报道，HRI是必要的，不仅在缺铁性贫血，而且在地中海贫血的严重程度降低。事实上，HRI在小鼠模型中引起了最激烈的修饰反应。地中海贫血。HRI通过磷酸化eIF2介导这种保护作用？抑制蛋白质合成，包括？？防止珠蛋白过度积累？球蛋白总量。因此，HRI及其下游底物可能是开发严重地中海贫血新疗法的潜在药物靶点。本提案的具体目的是：(1)测试和评估salubrinal的可行性，salubrinal是一种特异性用于eIF2？P在降低Hbb-/- ?？地中海贫血红细胞前体；(2)筛选能调节HRI应激反应途径和减少细胞凋亡的化合物。地中海贫血的红细胞前体。我们将使用HRI缺乏的复合小鼠和？？主要珠蛋白基因作为一种严重地中海贫血的模型。我们将研究salubrinal是否能增加eIF2?？P水平下降了吗？-珠蛋白的合成和聚集，并减少小鼠地中海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？？筛查能够保护红细胞前体存活的化学物质。候选化合物在？？地中海贫血将被调查。这些研究的结果可能会导致发现新的化合物，不仅治疗地中海贫血，也治疗一般的红细胞疾病。公共卫生相关性：这项拟议研究的目的是进一步了解血红蛋白突变引起的贫血病理。这项研究也可能导致新的药物治疗红细胞疾病的发现。

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.