Keratin intermediate filaments (IFs) confer mechanical stability and stress protection to epithelial cells, and modulate many cellular functions, including protein targeting and maintenance of epithelial polarity. Keratins are also important for colon health, as revealed in keratin 8 knockout (K8‒/‒) mice, which exhibit Th2-type colitis, colonic hyperproliferation, diarrhea and mistargeting of ion transporters. The molecular mechanisms of how keratin IFs regulate colon homeostasis and health are, however, incompletely understood. The central aim of my research is to study how keratins regulate colon homeostasis. In particular, I'm interested in how keratin intermediate filaments participate in the regulation of intracellular architecture, protein targeting, energy metabolism, Ca2+ signaling and nuclear shape and function in colon epithelial cells.
- Animal models of intestinal diseases, including K8-null and K8-null heterozygous null mice and the DSS (chemical model of colitis) and AOM (model for colorectal cancer) models.
- Novel non-invasive in vivo intestinal image analysis techniques detecting reactive oxygen species.
- Intestinal epithelial cell culture models (e.g. siRNA, Lentiviral shRNA, Crisper/Cas9 and organoid culture technology),
- High resolution imaging techniques (http://www.bioimaging.fi/)
- Basic cell biologial, molecular and biochemical methods
- Advanced imaging techniques
- Animal models of diseases.
Helenius, T.O., Antman, C.A., Asghar, M.N., Nyström, J.H., Toivola, D.M. Keratins Are Altered in Intestinal Disease-Related Stress Responses. Cells. 2016 Sep 10;5(3). pii: E35. doi: 10.3390/cells5030035.
Misiorek, J.O., Lähdeniemi, I.A.K., Nyström, J.H., Paramonov, V.M., Gullmets, J.A., Saarento, H., Rivero-Müller, A., Husøy, T., Taimen, P., Toivola, D.M. Keratin 8-deletion induced colitis predisposes to murine colorectal cancer enforced by the inflammasome and IL-22 pathway. Carcinogenesis. 2016 Aug;37(8):777-86. doi: 10.1093/carcin/bgw063.
Asghar, M.N.*, Priyamvada, S.*, Nyström, J.H., Natarajan Anbazhagan, A., Dudeja, P.K.#, Toivola, D.M.#. Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon. Am. J. Physiol. Gastrointest. Liver Physiol. 28 April 2016, DOI: 10.1152/ajpgi.00354.2015. * # shared authorship
Strnad, P.*, Guldiken N., Helenius T.O., Misiorek, J.O., Nyström, J.H., Lähdeniemi, I.A.K, Silvander, J.S.G., Kuscuoglu, D., Toivola, D.M.*. Simple Epithelial Keratins. Methods Enzymol. 2016;568:351-88. doi: 10.1016/bs.mie.2015.08.004.
Helenius, T.O.*, Misiorek J.O.*, Nyström J.H.*, Fortelius L.E., Habtezion A., Liao J., Asghar, M.N., Zhang H., Azhar S., Omary M.B., Toivola D.M. Keratin 8 absence down-regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism. Mol Biol Cell. 2015 Jun 15;26(12):2298-310. doi: 10.1091/mbc.E14-02-0736. Epub 2015 Apr 22. * Shared first-authorship.