Understanding Acrodysostosis type 1 and 2 through a pluripotent stem cell-disease model.

肢端骨发育不全是一种非常罕见的疾病。症状可能因患者而异，但总是影响骨骼。肢端骨发育不全患者比平均水平矮，并且有一些骨骼异常，包括小手指和脚趾，这是因为他们的骨骼不能正常生长。骨骼的生长是由一种叫做“生长板软骨”的发育组织对激素的反应控制的，激素控制着骨骼的形成和生长。肢端发育不全患者携带的基因突变，控制生长板软骨如何响应这些激素。在我们的实验室中，我们已经开发出一种方法，在试管中从干细胞中生长人类生长板状软骨。我们还产生了人类干细胞系和方法，使基因的控制和特定的变化。在这个项目中，我们将在干细胞中创建肢端发育不全的基因突变，然后生成生长板软骨组织，该组织将携带与肢端发育不全相关的基因缺陷。然后，我们将比较该组织与未受影响的干细胞（没有遗传改变）产生的组织，以确定为什么肢端发育不全影响的生长板软骨对生长诱导激素的反应不同。通过全面观察细胞中产生的携带所有不同蛋白质编码的RNA分子，我们可以在分子水平上确定肢端发育不全的软骨形成中出现了什么问题。从这项研究中，我们希望确定几种没有形成的分子，在错误的时间形成或过量形成，并可能导致疾病。这些问题可以在今后的工作中使用药物加以纠正。因此，这项研究预计将指出潜在的药物，可以评估治疗肢端发育不全。

Acrodysostosis is a very rare disease. Symptoms can differ from patient to patient but always affect the skeleton. Acrodysostosis patients are shorter than average and have some skeletal abnormalities including small fingers and toes, this is because their bones do not grow properly. Bone growth is controlled by how a developing tissue called 'growth plate cartilage' responds to hormones which control the formation and growth of the skeleton. Acrodysostosis patients carry genetic mutations in the genes that control how growth plate cartilage responds to these hormones. In our lab we have developed a way to grow human growth plate-like cartilage from stem cells in a test tube. We have also generated human stem cell lines and methods to make controlled and specific changes in genes. In this project we will create the Acrodysostosis genetic mutations in stem cells and then generate growth plate cartilage tissue that will carry the genetic defects associated with Acrodysostosis. We will then compare this tissue to that generated from unaffected stem cells (without the genetic alteration) to determine why Acrodysostosis-affected growth plate cartilage responds differently to the growth-inducing hormones. By looking globally at the RNA molecules made in the cell which carry the codes for all the different proteins, we can identify what has gone wrong in cartilage formation in Acrodysostosis at the level of molecules. From this research we expect to identify several molecules which are not formed, formed at the wrong time or in excess and likely cause disease. These could be corrected in future work using drugs. Thus, this research is expected to point to potential drugs which can be evaluated for the treatment of Acrodysostosis.