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

肢端骨发育不良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。肢端畸形患者比一般人矮，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没有正常生长。骨骼的生长是由一种叫做“生长板软骨”的发育组织对控制骨骼形成和生长的激素的反应所控制的。肢端畸形患者携带着基因突变，这些基因控制着生长板软骨对这些激素的反应。在我们的实验室里，我们已经开发出一种在试管中从干细胞中培养人类生长板状软骨的方法。我们还培育了人类干细胞系，并找到了对基因进行控制和特定改变的方法。在这个项目中，我们将在干细胞中产生肢端畸形基因突变，然后产生生长板软骨组织，该组织将携带与肢端畸形相关的遗传缺陷。然后，我们将该组织与未受影响的干细胞（没有基因改变）产生的组织进行比较，以确定为什么受肢端骨不全影响的生长板软骨对生长诱导激素的反应不同。通过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识别出肢端畸形软骨形成过程中出现的问题。从这项研究中，我们希望确定一些未形成的分子，在错误的时间形成或过量形成，并可能导致疾病。这些可以在未来的工作中通过药物加以纠正。因此，这项研究有望指出潜在的药物，可以评估治疗肢端畸形。

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.