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

描述（由申请人提供）：血红蛋白病镰状细胞病和？地中海贫血是全世界最常见和最具破坏性的遗传疾病之一。在卫生保健系统发达的国家，对受影响者的护理极其昂贵;在发展中国家，大多数受影响者得到的护理低于标准或得不到护理，儿童死亡很常见。人们早就知道，（胎儿）？珠蛋白的表达可以改善或预防这两种疾病，如？珠蛋白替代品的缺陷？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目标，但很难设计出有效的高通量检测方法。在这里，我们建议开发一种检测方法，可以产生具有逆转活性的候选化合物。成熟期红细胞中的珠蛋白沉默。这是一种基于细胞的检测方法，依赖于PI开发的尝试方法的新应用;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类别的线索，并且可以在再现珠蛋白转换的实验系统中测试特定活性。这是一项旨在开发和探索该检测方法的试点研究，但初步测试表明，它能够识别具有先前未描述的表观遗传活性的化合物。因此，这项研究可以为解决一个顽固问题开辟一条新的途径，解决这个问题可能会影响到全世界数百万人的生活。公共卫生相关性：镰状细胞病和地中海贫血是毁灭性的遗传性疾病，在世界范围内非常常见，在美国也越来越常见;目前对它们的医学治疗是不充分和昂贵的。一种能够重新激活胎儿珠蛋白表达的廉价而有效的药物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的负担。该提案提出了一种寻找可能提供这种廉价有效治疗的化合物的新方法;因此，它有可能对公共卫生产生广泛影响。

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.