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

基本信息

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
项目类别：
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

项目摘要

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）： - - 血红蛋白病细胞疾病和？ - 丘陵症是全球最常见，最具毁灭性的遗传疾病之一。在具有发达医疗保健系统的国家，对受影响个人的护理非常昂贵。在发展中国家，大多数受影响的人都会受到不合格或没有照顾，而童年的死亡很普遍。早就知道，增强（胎儿）的产生吗？ - 珠蛋白表达可以改善或预防这两种疾病，例如？ - 斑蛋白替代有缺陷的？ - globin。长期以来一直在寻求一种安全有效的药物，但是很难设计有效的高通量测定法。在这里，我们建议开发一种可能产生候选化合物在逆转的候选化合物？ - 成人红细胞中的珠蛋白沉默。这是一种基于细胞的测定法，依赖于PI开发的新方法的新应用；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的导致，并且可以在重现球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测定法的试点研究，但最初的测试表明，它能够鉴定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顽固问题的方法开放新的方法，该解决方案可能会影响全球数百万的生命。公共卫生相关性：镰状细胞疾病和_-丘脑贫血是毁灭性的遗传疾病，在全球范围内非常普遍，在美国越来越普遍；当前对他们的医疗不足和昂贵。一种可以重新激活胎儿球蛋白表达的廉价药物将对这些疾病的全球发病率和死亡产生重大影响，并减轻许多发展中国家的医疗保健系统的巨大负担。该提案提出了一种新的方法来寻找可能提供如此廉价和有效治疗的化学化合物。因此，它有可能对公共卫生产生广泛影响。