MICA: Calcium signalling, organelle dysfunction and pancreatitis

The pancreas secretes the enzymes needed for the breakdown in the gut of proteins, fats and carbohydrates. However, the enzymes needed for digestion can, if inappropriately activated inside the cells in the pancreas, also digest the pancreas itself. This is what happens in the painful human disease acute pancreatitis, which is mostly caused by gallstones and excessive alcohol intake. The incidence has been steadily increasing over the last 25 years in both the UK and the US (now about 100 per 100,000 people per year) and there is a significant mortality (about 5%). The NHS expenditure on intensive care treatment for acute pancreatitis is more than £100 million per year. There is currently no specific therapy. Repeated attacks of acute pancreatitis may lead to chronic pancreatitis, which increases markedly the risk of developing pancreatic cancer. In the UK there are ~8000 patients diagnosed annually with pancreatic cancer, which has the lowest 5-year survival (about 3%) of all common cancers. So far, there has been disappointingly little progress with regard to prevention and treatment of this cancer.
We have recently shown that the digestive enzyme activation inside the cells, which starts the process leading to acute pancreatitis, is due to excessive release of calcium ions from internal stores and have identified the molecules which allow this transport. We have also discovered an unexpected intrinsic protective mechanism due to a calcium-binding molecule, which is normally present inside cells. Most importantly, we have been able to use a specific calcium-like molecule to boost the intrinsic protection against inappropriate enzyme activation inside the pancreatic cells. These recent findings promise new opportunities for the development of preventive and therapeutic measures and this is the basis for the work programme proposed.
We plan systematic tests of the ability of calcium-like molecules to protect against enzyme activation inside the enzyme-producing cells in the pancreas under a variety of circumstances relevant to the real disease situation. These studies will involve experiments on isolated cells and small cell clusters as well as larger pieces of pancreas in which the protective effects of calcium-like molecules against the actions of a variety of agents known to start the process of developing pancreatitis (fatty acids and combinations of fatty acids and alcohol, alcohol alone as well as bile acids) will be tested.
Release of calcium ions inside cells and flow of calcium ions into the cells from the outside are complex processes. We are aiming at identifying critical control points and ways and means of interfering with these, to develop additional strategies for prevention and/or treatment of acute pancreatitis.
An entirely novel aspect of the work proposed is a study of a special cell type in the pancreas called the stellate cell. Stellate cells are known to become activated during the development of chronic pancreatitis and are responsible for the production of the so-called stromal matrix - a complex of fibres and substances secreted into the spaces between cells - which is critically important for the development of pancreatic cancer. It is therefore essential to understand the mechanisms by which these stellate cells are controlled in order finally to be able to make progress with prevention and treatment of pancreatic cancer. Calcium ions are known to be important for stellate cell function, but the detailed mechanisms of their transport and function in these cells are obscure and almost nothing is known about nervous control. Building on the detailed knowledge and experience we have developed in work on calcium ion - dependent control of the enzyme-secreting cells in the pancreas, we shall now study the nervous and chemical control of stellate cells and develop procedures to inhibit their excessive secretion of cancer-promoting materials.

Acute pancreatitis is a sometimes fatal human disease in which the pro-enzymes synthesized in the pancreatic acinar cells are activated inside the cells (rather than after they have been secreted into the gut) and digest the pancreatic tissue (rather than the food in the gut). It is mostly caused by gallstones or excessive alcohol intake. Repeated attacks may lead to chronic pancreatitis, which increases markedly the risk of developing pancreatic cancer. There is currently no specific therapy for pancreatitis.
We have recently identified molecules in the acinar cells responsible for the excessive intracellular Ca2+ release elicited by agents causing pancreatitis and been able to knock-out of these molecules and thereby prevent the fatal intracellular protease activation. Furthermore, we have discovered that a normally present intracellular molecule, calmodulin (CaM), exerts a protective action and found that application of a membrane-permeable Ca2+-like peptide can boost this protection.
We now plan to test systematically the CaM-dependent mechanisms for inhibiting excessive intracellular Ca2+ release elicited by all the major known agents inducing pancreatitis. We shall specifically test the ability of Ca2+-like peptides to protect against intracellular protease activation using realistic mouse models of the disease.
We also plan novel studies of a special cell type, namely the pancreatic stellate cell (PSC). Activated PSCs drive development of chronic pancreatitis and are responsible for production of the cancer-promoting stromal matrix. Intracellular Ca2+ is involved, but the mechanisms of Ca2+ transport and function in PSCs are obscure and essentially nothing is known about nervous control. Building on our experience with Ca2+- dependent control of the acinar cell function, we shall study nervous and chemical control of PSCs in mouse pancreatic lobules and test procedures to inhibit their excessive secretion of cancer-promoting materials.

Our work will advance understanding of the mechanisms promoting acute and chronic pancreatitis and therefore also pancreatic cancer. Our work may also lead to a better understanding of the risks of pancreatic disease associated with various diets and to identification of agents (drugs) that can prevent or treat these diseases.

The beneficiaries of this research are therefore patients suffering from or at risk of developing pancreatic disease. It is inevitably difficult to predict the timescales involved. Although pancreatitis has been a well recognized disease for very many years, there has essentially been no progress up to now with regard to therapy and it is generally accepted that acute pancreatitis is currently untreatable. With regard to pancreatic cancer there has also - unlike many other cancers - been essemtially no progress.

We believe that we have now made robust findings, identifying specific molecular pathways responsible for the initiation of acute pancreatitis, and this makes it likely that by interfering with these now well defined processes we can develop specific helpful measures. It is our hope that within the 5-year grant period we shall have established in animal models clear and well defined procedures for prevention and/or treatment of pancreatitis, which can then be tested in the clinic.