A high-throughput screen for candidate agents that may reverse gamma-globin silen

高通量筛选可能逆转伽马珠蛋白沉默的候选药物

• 批准号: 7851313
• 负责人: David Ian Kingston Martin
• 金额: $ 20万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851313
• 关键词: Acute Erythroblastic Leukemia; Adult; Affect; Aliquot; Biological Assay; Biological Models; Caring; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Chemicals; Childhood; Chromatin; Clone Cells; Country; Culture Media; Developing Countries; Disease; Epigenetic Process; Erythrocytes; Erythroid Cells; Eukaryota; Failure; Fluorescence-Activated Cell Sorting; Genes; Genome; Genomics; Globin; Goals; Healthcare Systems; Hemoglobinopathies; Hereditary Disease; Histone Deacetylase Inhibitor; Individual; Lead; Life; Mammalian Cell; Medical; Methodology; Methods; Molecular; Morbidity - disease rate; Mus; Nature; Pharmaceutical Preparations; Pilot Projects; Procedures; Production; Public Health; Publishing; Reporter; Reporter Genes; Safety; Screening procedure; Sickle Cell Anemia; Site; Solutions; Sorting - Cell Movement; Staging; System; Testing; Thalassemia; Therapeutic Agents; Transgenes; base; cell type; early childhood; effective therapy; erythroid differentiation; experience; fetal globin; gamma Globin; high throughput screening; mortality; novel; prevent; public health relevance; response; scale up; small molecule libraries; tool; transgene expression

DESCRIPTION (provided by applicant): The ?-hemoglobinopathies sickle cell disease and ?-thalassemia are among the most common, and most devastating, genetic diseases worldwide. In countries with developed health care systems, care for affected individuals is extremely expensive; in developing countries most affected individuals receive substandard or no care, and death in childhood is common. It has long been known that enhanced production of (fetal) ?-globin expression can ameliorate or prevent both diseases, as ?-globin substitutes for the defective ?-globin. A safe and effective drug that will accomplish this has long been sought, but it has been difficult to devise effective high-throughput assays. Here we propose to develop an assay that may produce candidate compounds that have activity in reversing ?-globin silencing in adult-stage red blood cells. This is a cell-based assay that relies on a new application of tried methodology developed by the PI; it is capable of screening many thousands of compounds. These compounds may serve as leads to new classes of active molecules, and can be tested for specific activity in experimental systems that reproduce globin switching. This is a pilot study intended to develop and explore the assay, but the initial testing has revealed that it is capable of identifying compounds with previously undescribed epigenetic activity. This study could thus open a new avenue of approach to a stubborn problem, the solution to which could affect millions of lives worldwide. PUBLIC HEALTH RELEVANCE: Sickle cell disease and _-thalassemia are devastating genetic diseases that are extremely common worldwide and increasingly common in the USA; current medical treatment for them is inadequate and expensive. A cheap and effective drug that could reactivate fetal globin expression would have a major impact on worldwide morbidity and mortality from these diseases, and ease a considerable burden on the health care systems of many developing countries. This proposal presents a new method of searching for chemical compounds that might provide such a cheap and effective treatment; thus it has a potential for a broad impact on public health.

描述(由申请人提供)：？-血红蛋白病、镰状细胞病和？-地中海贫血是世界上最常见、最具破坏性的遗传病。在卫生保健系统发达的国家，对受影响的个人的护理极其昂贵；在发展中国家，大多数受影响的个人得到的护理不达标或没有得到护理，儿童死亡很常见。人们早就知道，增加(胎儿)-珠蛋白的表达可以改善或预防这两种疾病，因为-珠蛋白替代了有缺陷的？-珠蛋白。长期以来，人们一直在寻找一种安全有效的药物来实现这一点，但一直很难设计出有效的高通量分析方法。在这里，我们建议开发一种可能产生候选化合物的方法，这些化合物可能具有逆转成年阶段红细胞中的珠蛋白沉默的活性。这是一种基于细胞的分析，依赖于PI开发的成熟方法学的新应用；它能够筛选数千种化合物。这些化合物可以作为新的活性分子的先导，并可以在重现珠蛋白开关的实验系统中进行特定活性的测试。这是一项试验性研究，旨在开发和探索这种分析方法，但初步测试表明，它能够识别具有以前未描述的表观遗传活性的化合物。因此，这项研究可能会为解决一个棘手的问题开辟一条新的途径，这个问题的解决可能会影响到全球数百万人的生活。与公共卫生相关：镰状细胞病和地中海贫血是破坏性的遗传性疾病，在世界范围内极其常见，在美国越来越常见；目前对它们的治疗不足且费用高昂。一种廉价有效的药物可以重新激活胎儿珠蛋白的表达，将对这些疾病的全球发病率和死亡率产生重大影响，并减轻许多发展中国家卫生保健系统的相当大负担。这项提议提出了一种寻找化合物的新方法，这种化合物可能提供这样一种廉价而有效的治疗方法；因此，它有可能对公众健康产生广泛影响。