Stage de Master : Modeling developmental rare disorders in induced pluripotent stem cells: from single molecule to induced pluripotent stem cells (S. Bendahhou)

Team 1 proposed a Master project for 2019-2020. Andersen and fetal alcohol syndromes are complex developmental disorders that share many clinical phenotypes. This project will focus on determining the role of the Kir2.1 channel during bone morphogenesis in vitro and in vivo using patient biopsies, and animal models.

Andersen and fetal alcohol syndromes are complex developmental disorders that share many clinical phenotypes. The patients exhibit structural birth (short stature, wide set ears, cleft palate, digit abnormalities, dental anomalies) and cognitive defects. We have made progress understanding how mutations in the KCNJ2, the only gene associated with Andersen’s syndrome (AS), can lead to electrical dysfunctions in both skeletal and cardiac muscles. However, our understanding of the fundamental molecular and biophysical mechanisms responsible for Kir2.1 dysfunction is incomplete. Moreover, the contribution of Kir2.1 to bone development remains to be elucidated. Since AS and fetal alcohol syndromes (FAS) have common clinical phenotypes, it was hypothesized that the Kir2.1 could be a good molecular target.

The actual project will focus on determining the role of the Kir2.1 channel during bone morphogenesis in vitro and in vivo using patient biopsies, and animal models.

We have used these biopsies to understand the role of the potassium channels in both skeletal muscle excitability and bone morphogenesis (1,2). If muscle biopsies may be appropriate in addressing skeletal muscle issues, this may have some limitations in other tissues. Reprogramming of human somatic cells into induced pluripotent stem cells (iPSCs) is a new powerful technology that offers an attractive tool to model human developmental pathways (3). Furthermore, disease-specific iPSCs allow an unprecedented experimental platform for basic research as well as high-throughput screening (4). This may be particularly relevant for developmental disorders in which the effects on cells during the early life are not accessible. We will take advantage of the availability of the patient biopsies (along with biopsies from controls) to generate human AS-specific iPSCs (5,6). These human AS-specific iPSCs will be differentiated in vitro into skeletal muscle, cardiac muscle, or osteoblasts.

The combination of both in vitro (human cells) and in vivo (mouse) studies will allow to obtain converging data on the role of Kir2.1 during mammalian development. The study will involve cell culture, cellular biology and biochemical techniques.

A thorough understanding of the Kir2.1 pathophysiology may facilitate the development of gene or drug therapies to better treat bone abnormalities.

 

1- Sacconi S, et al. (2009) Am J Physiol 297: C876-C885.

2- Sacco S, et al. (2015) Hum Mol Genet 24: 471-479.

3- Takahashi K, et al. (2007) Cell 131: 861-872.

4- Park IH, et al. (2008) Cell 134: 877-886.

5- Pini J, et al. (2016) Stem Cells Dev 25: 151-159

6- Pini J, et al. (2018) J Bone Miner Res 33 : 1826.

 

Cellules souches, différentiation

Canaux ioniques et transporteurs membranaires

Pathologie humaine

Signalisation moléculaire

Physiologie