The Role of Alpha Hemoglobin Stabilizing Protein in Human Beta Thalassemia

描述（由申请人提供）：我们正致力于从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。这种疾病的一个特征是过度自由？血红蛋白（Hb），一种不稳定的蛋白质，产生活性氧（ROS）并形成细胞毒性沉淀。我们鉴定了α血红蛋白稳定蛋白（AHSP），这是一种丰富的红系蛋白，可提高游离血红蛋白的溶解度。并限制其生化反应性。Ahsp-/-小鼠表现为溶血性贫血，伴有Hb沉淀和过量ROS。此外，AHSP的丧失加剧了？小鼠地中海贫血，提高了AHSP功能或表达改变可能调节？地中海贫血在人类中的表型。初步数据支持这两种机制。首先，我们发现了一种自然发生的错义突变AHSP N75I，它损害了蛋白质功能，并与两个家系中意想不到的严重地中海贫血有关。其次，AHSP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，在几项针对小地中海贫血队列和家系的独立研究中，AHSP表达减少与更严重的临床疾病相关。总之，这些发现导致了AHSP是一种基因修饰因子的假设。地中海贫血。我们将通过分析地中海贫血人群的AHSP基因突变，包括N75I，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，我们将研究红系AHSP表达的变化如何影响新生儿？地中海贫血患者血红蛋白池、氧化应激和临床严重程度我们的发现应该为正常红细胞生成的机制和病理生理提供新的见解？地中海贫血。最终，这些信息可以为开发新的治疗方法提供基础，以减轻游离？他在吗？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.