创新筛查方法确定致命儿童疾病可能的新治疗方法

(纽约，纽约)——许多导致人类疾病的基因在其他生物体中也有类似的基因，包括酵母。现在，哥伦比亚大学的研究人员已经使用一种创新的基于酵母的筛选方法来确定致命的儿童疾病尼曼-皮克C (NP-C)的可能治疗方法。这种“加重-逆转”的方法有可能用于研究任何疾病。该研究结果发表在2011年4月13日的《生物化学杂志》网络版上，并被编辑委员会和副编辑选为“本周论文”。NP-C是一组被称为脂质储存障碍的遗传病之一。脂质是存在于人体所有细胞中的类脂肪物质(包括脂肪和胆固醇)。患有NP-C，脂质代谢不正常会导致危险水平的脂质积聚在肝脏、脾脏和大脑中。NP-C是一种常染色体隐性遗传病;也就是说，父母双方都有缺陷基因，他们的孩子才会患上这种疾病。可悲的是，一对夫妇可能有几个孩子才意识到他们是携带者。 Some families have lost three out of four children to the disease. NP-C is a rare but devastating disease. The symptoms, which usually appear between the ages of four and ten, begin with problems with balance and gait, slurred speech, and developmental delays and inevitably progress to severe cognitive decline, dementia, and, ultimately, death. Frustrated families may spend several years seeking a proper diagnosis, when symptoms are misattributed to learning disabilities or “clumsiness.” Stephen L. Sturley, PhD, associate professor of clinical pediatrics, and Andrew B. Munkacsi, PhD, associate research scientist, both at Columbia University Medical Center, and their colleagues have shown that the existing cancer drug SAHA (developed by Columbia researchers) has the potential to improve three diagnostic criteria of NP-C: accumulation of cholesterol, 2) accumulation of sphingolipids, and 3) defective esterification of LDL-derived cholesterol (esterification is the formation of esters, fatty compounds derived from acids). The discovery of a new use for a drug already on the market is always good news, as the drug has already been tested for safety. Sturley and his team took advantage of the fact that the gene responsible for 95% of NP-C cases has been present throughout evolution, including in the evolutionarily distant yeast. They used what is called a “synthetic lethality screen” on a yeast model of NC-P. Synthetic lethality occurs when the combination of otherwise insignificant mutations in two or more genes leads to cell death. In other words, they determined which combination of mutations was lethal to the yeast. The cell nucleus contains proteins called histones. During histone acetylation, a group of atoms called an acetyl group is substituted for a hydrogen atom, and during histone deacetylation, it is removed. When deletion of genes responsible for histone acetylation in the yeast model led to an accumulation of lipids, the researchers hypothesized that an imbalance in histone acetylation caused NP-C disease. They found that the majority of the 11 histone deacetylase (HDAC) genes were impaired. They then discovered that the cancer drug, an HDAC inhibitor, repaired the genes. Sturley and his team concluded that the genetic pathways that exacerbate lethality in the yeast model could be reversed in human cells, providing a novel treatment for NP-C. In short, using their “exacerbate-reverse” approach, they identified the pathways that exacerbate lethality in their yeast model and then used drugs to manipulate those pathways in the opposite direction. The next step is to test this new use of the cancer drug on mice and, eventually, hopes Sturley, in clinical trials. Although scientific curiosity originally led Sturley to study NP-C, he is now motivated by the search for a cure. “Once you get to know some of these kids and their families,” he says, “it can’t be otherwise.” In addition to offering hope to NP-C sufferers and their families, research on NP-C and other lipid storage diseases may help scientists to understand the mechanisms of Alzheimer’s disease and other common dementias. -####- The study’s authors are: Andrew B. Munkacsi (CUMC); Fannie W. Chen (Mount Sinai School of Medicine); Matthew A. Brinkman (CUMC); Giselle Domínguez Gutiérrrz (CUMC); Jacob V. Layer (Indiana University-Purdue University); Amy Tong (University of Toronto); Martin Bard (Indiana University-Purdue University); Charles Boone (University of Toronto); Yiannis A. Ioannou (Mount Sinai School of Medicine); and Stephen L. Sturley (CUMC). The study was supported by the American Diabetes Association, the Ara Parseghian Medical Research Foundation, the DART Foundation, NIH, the Irving Institute for Clinical and Translational Science, and Genome Canada. The authors declare no financial or other conflict of interest.http://www.jbc.org/content/early/2011/04/13/jbc.M111.227645.full.pdf+html哥伦比亚大学医学中心在基础、临床前和临床研究方面处于国际领先地位;在医学和卫生科学教育方面;在病人护理方面。医学中心培养未来的领导者，并包括许多医生、科学家、公共卫生专业人员、牙医和护士在内科和外科医生学院、梅尔曼公共卫生学院、牙科医学院、护理学院、艺术与科学研究生院的生物医学部门以及相关的研究中心和机构的奉献工作。哥伦比亚大学内科和外科医学院成立于1767年，是美国第一个授予医学博士学位的机构，也是美国最挑剔的医学院之一。哥伦比亚大学医学中心是纽约市和纽约州最大的医学研究企业的所在地，也是美国最大的医学研究企业之一。欲了解更多信息，请访问www.cumc.columbia.edu．