The Role of Alpha Hemoglobin Stabilizing Protein in Human Beta Thalassemia

描述（由申请人提供）：我们正在努力朝着一个新的角度来理解和操纵？地中海贫血，一种常见的使人衰弱的遗传性贫血。这种混乱的一个标志是过度自由？血红蛋白（Hb），一种产生活性氧（ROS）并形成细胞毒性沉淀的不稳定蛋白质。我们确定了α血红蛋白稳定蛋白（α血红蛋白稳定蛋白），一种丰富的红细胞蛋白，提高游离？血红蛋白和限制其生化反应性。Ahsp-/-小鼠表现出具有Hb沉淀和过量ROS的溶血性贫血。此外，AHSP的丧失加剧了？地中海贫血的小鼠，提高了可能性，改变血红蛋白稳定蛋白的功能或表达可以调节？地中海贫血表型初步数据支持这两种机制。首先，我们发现了一个自然发生的错义突变，α-血红蛋白稳定蛋白N75 I，它损害蛋白质功能，并与两个家系中意想不到的严重β地中海贫血有关。第二，血红蛋白稳定蛋白似乎是一个数量性状位点（QTL），其表达在不同个体之间差异很大。此外，在几项小p地中海贫血队列和家系的独立研究中，α-血红蛋白稳定蛋白表达降低与更严重的临床疾病相关。总之，这些发现导致的假设，血红蛋白稳定蛋白是一种遗传修饰？地中海贫血我们将通过分析地中海贫血人群的α-血红蛋白稳定蛋白基因突变，包括N75 I，并确定其对基因表达和/或蛋白质功能的影响来验证这一点。此外，我们还将研究红系血红蛋白稳定蛋白表达的变化如何影响新生的？地中海贫血患者的血红蛋白池、氧化应激和临床严重程度。我们的研究结果应提供新的见解正常红细胞生成的机制和病理生理？地中海贫血最终，这些信息可以为开发新的治疗方法，以减轻毒性的自由？血红蛋白呢？地中海贫血

DESCRIPTION (provided by applicant): We are working toward a new perspective in understanding and manipulating the pathophysiology of ? thalassemia, a common and debilitating inherited anemia. A hallmark of this disorder is excessive free ? hemoglobin (Hb), an unstable protein that generates reactive oxygen species (ROS) and forms cytotoxic precipitates. We identified alpha hemoglobin stabilizing protein (AHSP), an abundant erythroid protein that enhances the solubility of free ?Hb and limits its biochemical reactivity. Ahsp-/- mice exhibit hemolytic anemia with Hb precipitates and excessive ROS. Moreover, loss of AHSP exacerbates ? thalassemia in mice, raising the possibility that altered AHSP function or expression could modulate ? thalassemia phenotypes in humans. Preliminary data support both mechanisms. First, we discovered a naturally occurring missense mutation, AHSP N75I, which impairs protein function and is associated with unexpectedly severe p thalassemia in two pedigrees. Second, AHSP appears to be a quantitative trait locus (QTL) whose expression varies considerably between different individuals. Moreover, reduced AHSP expression associates with more severe clinical disease in several independent studies of small p thalassemia cohorts and pedigrees. Together, these findings lead to the hypothesis that AHSP is a genetic modifier of ? thalassemia. We will test this by analyzing thalassemic populations for AHSP gene mutations, including N75I, and determining their effects on gene expression and/or protein function. In addition, we will study how variations in erythroid AHSP expression affect nascent ?Hb pools, oxidative stress and clinical severity in p thalassemic patients. Our findings should provide new insights into the mechanisms of normal erythropoiesis and the pathophysiology of ? thalassemia. Ultimately, this information could provide a basis for developing novel therapeutic approaches to mitigate the toxicities of free ?Hb in ? thalassemia.