Imperial College London
Alternate

ProfessorJuliaGorelik

Faculty of Medicine, National Heart & Lung Institute

Professor of Cellular Biophysics
 
 
 
//

Contact

 

+44 (0)20 7594 2736j.gorelik Website

 
 
//

Assistant

 

Miss Cheryl Costello +44 (0)20 7594 3001

 
//

Location

 

429ICTEM buildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Kondrashov:2021:10.1016/j.omtm.2020.10.019,
author = {Kondrashov, A and Mohd, Yusof NAN and Hasan, A and Goulding, J and Kodagoda, T and Hoang, DM and Vo, NTN and Melarangi, T and Dolatshad, N and Gorelik, J and Hill, SJ and Harding, SE and Denning, C},
doi = {10.1016/j.omtm.2020.10.019},
journal = {Molecular Therapy - Methods and Clinical Development},
pages = {39--53},
title = {CRISPR/Cas9-mediated generation and analysis of N terminus polymorphic models of β2AR in isogenic hPSC-derived cardiomyocytes},
url = {http://dx.doi.org/10.1016/j.omtm.2020.10.019},
volume = {20},
year = {2021}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - During normal- and patho-physiological situations, the behavior of the beta2-adrenoreceptor (β2AR) is influenced by polymorphic variants. The functional impact of such polymorphisms has been suggested from data derived from genetic association studies, in vitro experiments with primary cells, and transgenic overexpression models. However, heterogeneous genetic background and non-physiological transgene expression levels confound interpretation, leading to conflicting mechanistic conclusions. To overcome these limitations, we used CRISPR/Cas9 gene editing technology in human pluripotent stem cells (hPSCs) to create a unique suite of four isogenic homozygous variants at amino acid positions 16(G/R) and 27(G/Q), which reside in the N terminus of the β2AR. By producing cardiomyocytes from these hPSC lines, we determined that at a functional level β2AR signaling dominated over β1AR . Examining changes in beat rates and responses to isoprenaline, Gi coupling, cyclic AMP (cAMP) production, downregulation, and desensitization indicated that responses were often heightened for the GE variant, implying differential dominance of both polymorphic location and amino acid substitution. This finding was corroborated, since GE showed hypersensitivity to doxorubicin-induced cardiotoxicity relative to GQ and RQ variants. Thus, understanding the effect of β2AR polymorphisms on cardiac response to anticancer therapy may provide a route for personalized medicine and facilitate immediate clinical impact.
AU  - Kondrashov,A
AU  - Mohd,Yusof NAN
AU  - Hasan,A
AU  - Goulding,J
AU  - Kodagoda,T
AU  - Hoang,DM
AU  - Vo,NTN
AU  - Melarangi,T
AU  - Dolatshad,N
AU  - Gorelik,J
AU  - Hill,SJ
AU  - Harding,SE
AU  - Denning,C
DO  - 10.1016/j.omtm.2020.10.019
EP  - 53
PY  - 2021///
SN  - 2329-0501
SP  - 39
TI  - CRISPR/Cas9-mediated generation and analysis of N terminus polymorphic models of β2AR in isogenic hPSC-derived cardiomyocytes
T2  - Molecular Therapy - Methods and Clinical Development
UR  - http://dx.doi.org/10.1016/j.omtm.2020.10.019
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33335946
UR  - http://hdl.handle.net/10044/1/85747
VL  - 20
ER  -
Download