Biography

Biography: Julia Gerasimenko

Abstract

Novel approaches in combating pancreatitis and development of pancreatic cancer.

Julia Gerasimenko¹, Oleksiy Gryshchenko², Shuang Peng¹, Oleg Gerasimenko¹, Ole H Petersen¹.

¹Cardiff School of Biosciences, The Sir Martin Evans Building, Cardiff University, Cardiff CF10 3AX, Wales, UK; ²Bogomoletz Institute of Physiology, 4 Bogomoletz Street, Kyiv, 01024, Ukraine.

Acute pancreatitis (AP) is a dangerous and in up to 5% of cases deadly disease with no specific cure. The leading causes of acute pancreatitis have been identified as gallstone biliary disease and high alcohol intake, while abnormality in calcium signalling in pancreatic acinar cells (PACs) was found to be one of the first events.

We have shown previously that bile acids and non-oxidative alcohol metabolites elicit excessive Ca²⁺ release from intracellular stores. Subsequent intracellular Ca²⁺ store depletion activates the opening of Ca²⁺ release activated Ca²⁺ (CRAC) channels in the plasma membrane leading to Ca²⁺overload, premature activation of pancreatic pro-enzymes, digesting the pancreas and its surroundings.

Our recent work using a pancreatic lobule preparation allowed us to investigate potential role for pancreatic stellate cells (PSCs) in AP. AP often results in development of chronic pancreatitis (CP) and increased occurrence of pancreatic cancer (PC). The most common form of PC is pancreatic ductal adenocarcinoma and CP patients are at significant risk of developing PC. Activation of PSCs - during pancreatic injury - induces proliferation as well as secretion of extracellular matrix components, thereby playing an important role in the fibrosis that occurs in CP and PC.

PSCs generate substantial Ca²⁺ signals when challenged with both physiologically and pathologically relevant bradykinin (BK) concentrations by activation via bradykinin receptor type 2 (B2). The major plateau phase of these signals can be markedly reduced by CRAC channel inhibition and, importantly, blockade of PSCs B2 markedly diminishes the extent of acinar necrosis evoked by AP-inducing agents.

Our study indicates that combined treatment of pancreatitis with inhibitors of CRAC channels and B2 receptors could be potentially useful against development of PC. This study is beneficial for understanding of new mechanisms that could help combatting AP, transition to CP and development of PC.

References:

Gerasimenko et al. (2011) Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca²⁺ release through IP₃ receptors. PNAS, 108(14):5873-5878.

Gerasimenko et al. (2013) Ca²⁺ release-activated Ca²⁺ channel blockade as a potential tool in antipancreatitis therapy. PNAS, 110(32):13186-13191

Gerasimenko et al. (2014) The role of Ca²⁺ in the pathophysiology of pancreatitis. J Physiol. 592(2):269-280.

Gryshchenko et al. (2016) Ca²⁺ signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca²⁺ channel blockade. J Physiol. 594(2):281-293.

Ferdek PE, Jakubowska MA, Gerasimenko JV, Gerasimenko OV, Petersen OH (2016) J Physiol.  594(21):6147-6164.

Jakubowska MA, Ferdek PE, Gerasimenko OV, Gerasimenko JV, Petersen OH. 2016 Nitric oxide signals are interlinked with calcium signals in normal pancreatic stellate cells upon oxidative stress and inflammation. Open Biol. 2016 6(8). pii: 160149.