MicroRNAs (miRNAs) are small non-coding RNAs that mediate either translational repression or degradation of the target mRNA and constitute a novel mechanism for the regulation of smooth muscle phenotype. They are estimated to regulate up to one third of the human genome and to play a fundamental role in human disease. Our work is aimed at defining their roles by identifying miRNAs that are specifically expressed in smooth muscle and by investigating vascular effects of their knockout.
Hypothesis: Phenotypic modulation, and by extension vascular remodelling, is affected by miRNAs expressed in smooth muscle cells.
Objectives: We will identify miRNAs that are differentially regulated during remodelling of small arteries. Remodelling will be induced in vivo by partial obstruction of the saphenous artery or by transverse aortic constriction, creating low- and high-pressure sides in the same animal. Experiments will be performed in wild-type mice as well as in mice deficient of all miRNAs 1,2 or specific miRNAs (miR-143/145), which are highly expressed in smooth muscle. These are currently available in our laboratory. Genetic models of hypertension will be studied together with AMC. MicroRNA/mRNA-arrays and qPCR will be used to identify miRNAs that are differentially expressed in remodelled vs. control arteries. Targets of specific miRNAs will be identified by computational predictions and overexpression of mimics and inhibitors in combination with results from mRNA arrays.
Training: The ESR will be trained to work on miRNA expression changes and their importance in remodelled arteries. Training in analysis of vascular remodelling in vitro and in vivo will be provided in association with partners HML, DMT and VIS. The work will involve close collaboration with partner 1 on miRNAs in hypertension, with partner UP on in vivo models of hypertension and with partner WWU on miRNAs that regulate the matrix composition in small arteries.
1 Albinsson S et al. Arterioscl Thromb Vasc Biol 2010:1118-26, 2 Turczynska KM et al. J Biol Chem 2012;287:19199-206.
Krawczyk, K.K., Ekman, M., Rippe, C., Grossi, M., Nilsson, B.O., Albinsson, S., Uvelius, B., & Swärd, K. (2016). Assessing the contribution of thrombospondin-4 induction and ATF6α activation to endoplasmic reticulum expansion and phenotypic modulation in bladder outlet obstruction. Sci. Rep., 6, 32449. doi: 10.1038/srep32449.
Krawczyk, K.K., Yao Mattisson, I., Ekman, M., Oskolkov, N., Grantinge, R., Kotowska, D., Olde, B., Hansson, O., Albinsson, S., Miano, J.M., Rippe, C., & Swärd, K. (2015). Myocardin Family Members Drive Formation of Caveolae. PLoS One. doi: 10.1371/journal.pone.0133931.
Sadegh, M.K., Ekman, M., Krawczyk, K.K., Svensson, D., Göransson, O., Dahan, D., Nilsson, B.O., Albinsson, S., Uvelius, B., & Swärd, K. (2015). Detrusor induction of miR-132/212 following bladder outlet obstruction: association with MeCP2 repression and cell viability. PLoS One. doi:10.1371/journal.pone.0116784.
Krawczyk, K.M., Hansson, J., Krawczyk, K.K., Swärd, K., & Johansson, M. Induction of tubular caveolin-1 expression in sclerotic human kidneys – role of MKL1. (submitted)
Kodroń, A., Chanim, M., Krawczyk, K.K., Tońska, K., Stelmaszczyk-Emmel, A., Demkow, U., & Bartnik, E. Mitochondrial DNA polymorphisms in pediatric leukemia patients. (submitted)
Albinsson, S., Della Corte, A., Alajbegovic, A., Krawzczyk, K.K., Bancone, C., Galderisi, U., Cipollaro, M., De Feo, M., Forte, A. (2017). Patients with bicuspic and tricuspid aortic valve exhibit distinct regional microrna signatures in mildly dilated ascending aorta. Heart Vessels, doi: 10.1007/s00380-016-0942-7.
Ph.D student / post-doc
Prof. Karl Swärd