Chronic pancreatitis (CP) is characterized by inflammation, irreversible fibrosis, and necrosis of pancreatic parenchyma, resulting in exocrine and endocrine insufficiencies. Management of CP patients is particularly challenging due to poor understanding of its pathology, lack of reliable and definitive diagnostic markers and complete absence of therapeutics for interventions. The etiology of CP includes multiple genetic and environmental factors including alcohol, smoking, and high fat diet. Alcohol increases the lysosome and zymogen granules fragility and facilitates the pre-mature activation of proteolytic enzymes in acinar cells, resulting in auto-digestion. This recurring damage to parenchyma activates pancreatic stellate cells (PSC), leading to secretion of various cytokines, growth factors and extracellular matrix proteins likecollagens I, III, and IV, fibronectin, and laminin to promote fibrosis. In addition, pancreatic pathologies have characteristic mucin profile. Mucins (MUC) like MUC1, MUC5AC, MUC5B and MUC6 are upregulated during pancreatitis and shown to play critical role in inflammatory response. Studies have established that pancreatic acinar cells can metabolize alcohol both by oxidative and non-oxidative pathways. The products of ethanol oxidation and smoke exposure include aldehyde, reactive oxygen species, and fatty acid ethyl esters, all of which exert multiple toxic effects on pancreas. Aldehydes can make stable adducts with the intra- and extracellular proteins, modulate their function and are suggested to participate in tissue destruction and fibrosis, act as signaling molecules and elicit immunological response. However, the intricate mechanism and the precise contribution of aldehyde- Our preliminary studies have demonstrated the increase immunoreactivity of the aldehyde adducts (4HNE) in the pancreas of alcohol fed animals. Concurrently, smoke exposure significantly increased the activation of the PSC and upregulate the expression of SMA. herefore, the protein adducts in CP pathology remain elusive. T proposed study is based on the hypothesis that aldehyde protein-adducts mechanistically contribute to the progression of CP and can serve as potential diagnostic and prognostic markers.
Aim 1 : Identification and correlation of aldehyde-adducts with pathobiology of CP using murine models. Using appropriate CP mouse model, we will investigate the generation of protein adducts in the alcohol fed and smoke exposed animals and correlated them with the severity of the CP including necrosis, fibrosis, and extracellular matrix proteins. Simultaneously, we will evaluate the adduct formation on the mucins expressed during CP and will further evaluate their diagnostic and prognostic potential.
Aim 2 : Investigate the mechanistic contribution of aldehyde- adducts during CP using 3D co-culture system.
This aim will comprehend the mechanistic contribution of aldehyde- adducts on acinar and PSC cell biology. Taken together, the proposed studies will delineate the contribution of alcohol and smoking mediated proteins adducts in progression of CP that will provide novel diagnostic, prognostic, and therapeutic targets.
The management of chronic pancreatitis patients presents a great challenge because of poor understanding of its pathology. The proposed research seeks to mechanistically comprehend the role of alcohol in combination with smoking on the progression of chronic pancreatitis. The knowledge thus gained will provide novel diagnostic, prognostic, and therapeutic targets for intervention.
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| Cannon, Andrew; Thompson, Christopher; Hall, Bradley R et al. (2018) Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential. Genes Cancer 9:78-86 |
