The Role of Alpha Hemoglobin Stabilizing Protein in Human Beta Thalassemia

α 血红蛋白稳定蛋白在人类 β 地中海贫血中的作用

• 批准号: 7565891
• 负责人: Mitchell J Weiss
• 金额: $ 41.13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-19 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7565891
• 关键词: Affect; American; Anemia; Binding; Biochemical; Biology; Caring; Cells; Clinic; Clinical; Clinical Research; Code; Cooley' s anemia; Crystallography; Data; Databases; Disease; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Exhibits; Family; Frequencies; Functional disorder; Gene Expression; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Screening; Genotype; Geographic Locations; Globin; Haplotypes; Hemoglobin; Hemoglobinopathies; Hemolytic Anemia; Human; Impairment; Individual; Inherited; Investigation; Knowledge; Laboratories; Lead; Link; Longevity; Malaria; Measures; Membrane; Messenger RNA; Missense Mutation; Modification; Mus; Mutation; National Heart, Lung, and Blood Institute; Oxidation-Reduction; Oxidative Stress; Patients; Pediatric Hospitals; Peptides; Phenotype; Philadelphia; Population; Population Control; Population Study; Promoter Regions; Proteins; Quantitative Trait Loci; Reactive Oxygen Species; Recombinants; Research Personnel; Resistance; Role; Sampling; Severities; Single Nucleotide Polymorphism; Solubility; Structure; Sulfhydryl Compounds; Testing; Thalassemia; Thalassemia intermedia; Therapeutic; Toxic effect; Transferrin Receptor; Variant; Work; base; beta Thalassemia; cell injury; clinical phenotype; cohort; cytotoxic; diacetyldichlorofluorescein; genetic pedigree; insight; mRNA Expression; mutant; novel; novel therapeutic intervention; oxidation; programs; protein expression; protein function; protein structure; trait

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.

描述（由申请人提供）：我们正在努力理解和操纵病理生理学的新观点？ Thalassyia，一种常见且令人衰弱的遗传性贫血。这种疾病的标志是免费的吗？血红蛋白（HB）是一种产生活性氧（ROS）并形成细胞毒性沉淀物的不稳定蛋白。我们确定了α血红蛋白稳定蛋白（AHSP），这是一种丰富的红斑蛋白，可增强游离？Hb的溶解度，并限制其生化反应性。 AHSP - / - 小鼠表现出溶血性贫血，Hb沉淀和过度ROS。此外，AHSP的损失加剧了吗？小鼠的丘脑症，提高了改变AHSP功能或表达可能调节的可能性？人类的丘脑表型。初步数据支持这两种机制。首先，我们发现了一个天然存在的错义突变AHSP N75i，它会损害蛋白质功能，并与两个谱系中出乎意料的严重P talalsassia相关。其次，AHSP似乎是一个定量性状基因座（QTL），其表达在不同个体之间的变化很大。此外，在小型p thalassemia cohorts and Gedigrees的几项独立研究中，AHSP表达与更严重的临床疾病相关。总之，这些发现导致了AHSP是遗传修饰符的假设？地中海贫血。我们将通过分析包括N75i在内的AHSP基因突变的丘脑血症种群来测试这一点，并确定其对基因表达和/或蛋白质功能的影响。此外，我们将研究红斑AHSP表达的变化如何影响p thalassmic患者的氧化应激，氧化应激和临床严重程度。我们的发现应该提供有关正常红血病机制和病理生理学机制的新见解？地中海贫血。最终，这些信息可以为开发新型的治疗方法提供基础来减轻自由？HB的毒性？地中海贫血。