Role of calcium signalling in development of acute pancreatitis
PhD Research
Intake: October 2012
Funding:
The studentship is funded for 3 years by the Medical Research Council and includes payment of tuition fees and a tax free maintenance stipend for UK applicants. EU students are only eligible to have their tuition fees paid unless they have been resident in the UK for three years prior to the start date of the programme and then they are also entitled to receive the maintenance stipend. Unfortunately overseas applicants are not eligible to apply.
Primary Supervisor: Dr Oleg Gerasimenko (GerasimenkoOV@cf.ac.uk)
Secondary Supervisors: Dr Julia Gerasimenko (GerasimenkoJV@cf.ac.uk)
Project details:
Acute pancreatitis is characterised by premature activation of digestive enzymes inside the pancreatic acinar cells that leads to high levels of necrosis, digestion of the pancreatic tissue and its surroundings with no specific therapy (1). Pancreatitis is mostly caused by bile duct stones or excessive alcohol intake. Studies of calcium regulation can help to reduce the severity of acute pancreatitis (2). Recently we discovered a protective role of calmodulin against alcohol-induced calcium-dependent toxicity (3). Using newly designed calmodulin activators, we plan to investigate further the protective mechanism of calmodulin action against apoptosis/necrosis/autophagy induced by pancreatitis-and apoptosis-promoting agents (4,5) as well as in classical models of pancreatitis. The mechanism by which bile acids cause acute pancreatitis is poorly understood. We have shown previously that the bile acid taurolithocholic-acid-3-sulphate (TLCS) induces Ca2+ release from the endoplasmic reticulum and acid Ca2+ stores through nicotinic acid adenine dinucleotide phosphate (NAADP) receptors (6). A family of two pore channels (TPCN1/TPCN2) have been reported as the main candidates for mediating NAADP-elicited Ca2+ release from acid stores. We will investigate the potential involvement of NAADP-sensitive Ca2+ stores in the toxicity induced by bile acids using the novel selective inhibitor Ned-19 in control as well as TPCN2-/- and /TPCN1-/- mice. Using two-photon permeabilized cells (3,6) we will study the functional roles of NAADP receptors in TLCS action using TPCN1/2 knockout mice in combination with antibodies against NAADP receptor candidates.
References
1.Petersen_OH,Gerasimenko_OV,Gerasimenko_JV.(2011)F1000_Med_Rep:3:15.
2.Gerasimenko_JV,Lur_G, Sherwood_MW,et_al.(2009)PNAS:106(26):10758-63.
3.Gerasimenko_JV,Lur_G, Ferdek_P, Sherwood_MW,et al.(2011)PNAS:108(14):5873-8.
4.Baumgartner_HK,Gerasimenko_JV,Thorne_C,Ferdek_P,et_al.(2009)JBC:284(31):20796-803.
5.Gerasimenko_J,Ferdek_P,et_al.(2010)Pflugers Arch:460(5):891-900.
6.Gerasimenko_J,et_al.(2006)JBC:28:40154-63.
Eligibility Criteria:
The applicant must be eligible for UK/EU fee status and should hold a First or Upper Second Class Honours BSc degree and/or a Masters degree, or equivalent degree. If English is not the applicant's native language an English Language qualification, such as IELTS is required. For IELTS an average score of 6.5 is required with a minimum score of 6 in each element.
How to apply:
To fill in an application form see: http://www.cf.ac.uk/regis/general/applyonline/index.html