孤独症的一个更好的基因检测

骨髓衰竭可能开始比以前认为的更早

2010年3月2日

波士顿，大众。——孩子们范可尼贫血，一种遗传性疾病，可能是致命的骨髓移植的情况下，通常不经历低血细胞计数，直到约7岁。然而，通过在实验室中使用胚胎干细胞，研究人员在实验室的研究波士顿儿童医院揭示导致骨髓衰竭（不充分生产血细胞）的事件实际上可能在出生前就开始，在疾病中铸造一个全新的光。

为首的Tulpule，博士，博士生在儿童儿科血液\/肿瘤科，和干细胞研究员George Daley，医学博士，博士，主任的干细胞移植计划在儿童，来自人类胚胎干细胞（ESC）血细胞复制血液形成的最早阶段。如杂志报道血online on January 20，y then knocked down, or suppressed, two genes associated with 范可尼贫血, and demonstrated that the disease compromises the formation of blood cells from the earliest stages of human development。

"When we knock down these genes, you see a profound deficit in blood cell formation, suggesting that these genes have an important role in early blood development," says Tulpule, first author of the paper。 These results suggest that children with 范可尼贫血 are born with what is already a depleted pool of blood stem cells。

Previous research had failed to create a suitable laboratory model for 范可尼贫血。 Mouse models showed that the disease involves an inability to repair DNA damage, but the mice did not display the characteristic skeletal abnormalities, increased risk for leukemia or, most significantly， trademark bone marrow failure seen in humans。 Human ESCs proved to be a suitable model for observing the development of 范可尼贫血。

The researchers turned to existing lines of human ESCs to create their model because past research has indicated that it is difficult to generate 范可尼贫血 models from induced pluripotent stem (iPS) cells, which are made from the skin cells of patients。 Furthermore, scientists cannot create a disease model using a patient's blood stem cells, either。

"血 stem cells are not easy to get from patients," Tulpule says。 Because 范可尼贫血 depletes a child of blood stem cells, extracting them for testing is not practical。 "Human ESCs allow us to do all kinds of different studies that were unthinkable。"

范可尼贫血 is caused by a deletion of any of 13 genes。 In healthy cells, some of these genes manufacture a core complex of eight proteins responsible for DNA repair, and others manufacture proteins downstream of this core complex。 The researchers created a model using two of the genes。

After establishing human ESC cultures in the lab，y used RNA-interfering viruses to suppress the activity of FANCA, one of the genes in the DNA repair core complex and responsible for 65 percent of 范可尼贫血 cases, or FANCD2, a gene acting downstream of the core complex and responsible for up to 6 percent of cases。 After gene knockdown， ESCs were coaxed with a special brew of growth factors to become blood cells。

相比于胚胎干细胞，没有经过基因敲除，与任何一个或没有FANCA FANCD2击倒修复DNA损伤和不易分化为造血干细胞的细胞系，提供了强有力的证据表明，血液的形成是阻碍人类发展的最早阶段中。与FANCD2击倒细胞产生最少的造血干细胞，与更严重的疾病患者的突变的核心复合物的下游一致。

当研究人员重新插入两基因到细胞培养的胚胎干细胞，又能产生造血干细胞。

Based on their lab model， researchers now hypothesize that a child with 范可尼贫血 is born with far fewer blood stem cells than usual。 These limited stem cells are able to produce enough blood cells to make cell counts appear normal for years, but eventually， inability to repair DNA damage takes its toll。 These blood stem cells begin to die, making a bone marrow transplant the only recourse for a child。

该研究的下一步就是找出为什么FANCA，FANCD2基因和相关基因是血液的形成至关重要。初步的实验表明，这些基因与另一组基因称为Hox基因相互作用，这在血细胞和胚胎肢体图案的发展起到一定的作用。

The researchers' relative ease with their lab model shows how promising human ESCs are to understanding genetic diseases such as 范可尼贫血, Tulpule says。

"Using these cells allows us to have a better understanding of the disease and how to treat it," Tulpule says。 In the future, human ESCs could be used for drug screening, helping researchers find agents that prevent marrow loss and augment the blood's ability to carry oxygen。 Such treatments won't cure 范可尼贫血, but could keep a child alive long enough to wait for a bone marrow transplant, Tulpule says。

这项研究是由国立卫生研究院资助的Burroughs Wellcome基金，白血病和淋巴瘤协会，以及哈佛干细胞研究所。Daley的调查员休斯霍华德医学研究所。

引文：
Asmin Tulpule, M。 William Lensch, Justine D。 Miller, Karyn Austin, Alan D'Andrea, Thorsten M。 Schlaeger, Akiko Shimamura, George Q。 Daley。 Knockdown of 范可尼贫血 genes in human embryonic stem cells reveals early developmental defects in the hematopoietic lineage。血Jan。 20, 2010 (online)。

接触：
安德鲁斯伊丽莎白
617-919-3110
Elizabeth。Andrews@childrens。harvard。edu

波士顿儿童医院 is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869。 More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 13 members of the 休斯霍华德医学研究所 comprise Children's research community。 Founded as a 20-bed hospital for children, 波士顿儿童医院 today is a 397-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families。 Children's also is the primary pediatric teaching affiliate of Harvard Medical School。 For more information about the hospital and its research visit:www。childrenshospital。org/newsroom。

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