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

肢端营养不良是一种非常罕见的疾病。每个患者的症状可能不同，但总是会影响骨骼。肢端骨质疏松症患者身高低于平均水平，并有一些骨骼异常，包括小手指和脚趾，这是因为他们的骨骼不能正常生长。骨骼生长是由一种名为生长板软骨的发育组织如何对控制骨骼形成和生长的激素做出反应来控制的。顶端骨质疏松症患者携带基因突变，这些基因控制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方法，可以在试管中从干细胞中培养出人类生长板状软骨。我们还创造了人类干细胞系和方法，以对基因进行受控和特定的改变。在这个项目中，我们将在干细胞中创建肢端发育不良的基因突变，然后生成携带与肢端发育不良相关的遗传缺陷的生长板软骨组织。然后，我们将把这个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，以确定为什么肢端发育不良影响的生长板软骨对生长诱导激素的反应不同。通过全局观察细胞中制造的携带所有不同蛋白质密码的RNA分子，我们可以在分子水平上识别肢端发育不良症软骨形成中的问题。从这项研究中，我们希望识别出几个没有形成、在错误的时间形成或过量并可能导致疾病的分子。这些可以在未来使用药物的工作中得到纠正。因此，这项研究有望指出可以评估的治疗肢端发育不良的潜在药物。

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.