Keratins in intestinal  and endocrine pancreas health and disease

Organization:

Åbo Akademi University, Department of Biosciences, Cell biology, Biocity, Tykistökatu 6A, FI-20520 TURKU, Finland

Research group:

Catharina Alam, PhD; M. Nadeem Asghar, Lic/MPhil; Julia Misiorek, MSc; Terhi Helenius, MSc; Iris Lähdeniemi, MSc; Joel Nyström, MSc; Jonas Silvander, MSc; Sofie Kvarnström, BSc; Cecila Antman, BSc; Rickard Holmsten, BSc; Helena Saarento, MSc.

The goal of the projects:

Research in the intestinal disease unit located at Åbo Akademi University is focused on the roles and regulation of keratin intermediate filaments in gastrointestinal epithelia including the colon, small intestine, liver, as well as the endo- and exocrine pancreas. Keratins are cytoskeletal structures important in protection from cellular stress. Keratin mutations predispose humans to diseases, including liver disease and possibly inflammatory bowel disease (IBD). The keratin (K)8 knockout mouse obtains an early IBD/ulcerative colitis-phenotype. Our aims are to understand how keratins help protect simple type epithelia on a molecular level, in particular in gastrointestinal organs with focus on intestine and the endocrine pancreas. Using the K8 heterozygous and knockout mice, mice expressing keratin mutations, experimental models of colitis, colorectal cancer, diabetes, and cell systems, we study the role of keratins in e.g. stress, ion transport, protein and organelle targeting, cell proliferation and differentiation, colonocyte energy metabolism, cancer, regeneration and diabetes. We also aim to develop imaging modalieis to detect IBD in mice in vivo, and use nanomaterials to target drugs intestinal tissues. Webpage for the Epithelial biology laboratory at Åbo Akademi University: www.toivola-lab.org

Representative publications:

Lähdeniemi IAK, Misiorek JO, Antila CJM, Landor SK, Stenvall CA, Fortelius LE, Bergström LK, Sahlgren C, Toivola DM. Keratins regulate colonic epithelial cell differentiation through the Notch1 signalling pathway. Cell Death Differ. 2017 Jun;24(6):984-996.

Helenius TO, Antman CA, Asghar MN, Nyström JH, Toivola DM. Keratins Are Altered in Intestinal Disease-Related Stress Responses. Cells. 2016 Sep 10;5(3).

Misiorek JO, Lähdeniemi IAK, Nyström JH, Paramonov VM, Gullmets JA, Saarento H, Rivero-Müller A, Husøy T, Taimen P, Toivola DM. Keratin 8-deletion induced colitis predisposes to murine colorectal cancer enforced by the inflammasome and IL-22 pathway. Carcinogenesis. 2016 Aug;37(8):777-786.

Asghar MN, Priyamvada S, Nyström JH, Anbazhagan AN, Dudeja PK, Toivola DM. Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon. Am J Physiol Gastrointest Liver Physiol. 2016 Jun 1;310(11):G1147-54. doi: 10.1152/ajpgi.00354.2015.

Desai D, Prabhakar N, Mamaeva V, Karaman DS, Lähdeniemi IAK, Sahlgren C,  Rosenholm J, Toivola DM. Targeted Modulation of Cell Differentiation in Distinct Regions of the Gastrointestinal Tract via Oral Administration of Differently PEI-PEG Functionalized Mesoporous Silica Nanoparticles. Int. J. Nanomedicine, in press, November 2015.

Helenius TO, Misiorek JO, Nyström JH, Fortelius LE, Habtezion A, Liao J, Asghar MN, Zhang H, Azhar S, Omary MB, Toivola DM. Keratin 8 absence downregulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism. Mol Biol Cell, 26:2298-2310, 2015

Asghar MN, Silvander JS, Helenius TO, Lähdeniemi IA, Alam C, Fortelius LE, Holmsten RO, Toivola DM. The amount of keratin matters in stress protection of the colonic epithelium. PLoS One 10(5):e0127436, 2015

Asghar MN, Emani R, Alam C, Helenius TO, Grönroos TJ, Sareila O, Din MU, Holmdahl R, Hänninen A, Toivola DM. In vivo imaging of reactive oxygen and nitrogen species in murine colitis. Inflamm. Bowel Dis 20:1435-1447, 2014

Alam CM, Silvander JS, Daniel EN, Tao GZ, Kvarnström SM, Alam P, Omary MB, Hänninen A,Toivola DM. Keratin 8 modulates β-cell stress responses and normoglycaemia. J. Cell Sci. 126:5635-5644, 2013.

Habtezion A, Toivola DM, Asghar MN, Kronmal GS, Brooks JD, Butcher EC, Omary MB. Absence of keratin 8 confers a paradoxical microflora-dependent resistance to apoptosis in the colon.. Proc Natl Acad Sci USA, 108:1445-1450, 2011.

Toivola DM, Habtezion A, Strnad P, Omary MB. Intermediate filaments take the heat as stress proteins. Trends Cell Biol, 20:79-91, 2010.

Ku NO, Toivola DM, Strnad P, Omary MB. Cytoskeletal keratin glycosylation protects epithelial tissue from injury.Nat Cell Biol. 12:876-885, 2010.

Habtezion A, Toivola DM, Butcher EC, Omary MB. Keratin-8-deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment. J Cell Sci, 118:1971-1980, 2005.

Toivola DM, Krishnan S, Binder HB, Singh S, Omary MB. Keratins modulate colonocyte electrolyte transport via protein mistargeting. J Cell Biol, 164:911-921, 2004.

Toivola DM, Tao GZ, Habtezion A, Liao J, Omary MB. Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments. Trends Cell Biol, 15:608-617, 2005.

Principal Investigator

Diana M. Toivola, PhD
Adjunct Professor of Cell Biology ÅAU
Associate Professor

dtoivola(at)abo.fi

Diana Toivola
  • Gastrointestinal organs with focus on intestine and islets of Langerhans
  • Experimental models of colitis, colorectal cancer, diabetes