The objective of the present grant proposal is to demonstrate how inborn gene mutations can sensitize the pancreas to alcohol-induced injury and result in alcoholic pancreatitis. The specific hypothesis tested posits that alcohol and mutations that affect digestive enzyme folding synergize in promoting endoplasmic reticulum stress and causing progressive acinar cell damage. In this setting, the pancreas becomes more sensitive to insults and responds with acute attacks of inflammation (alcoholic acute pancreatitis) which eventually progress to chronic disease (alcoholic chronic pancreatitis). Our proposed studies will take advantage of a novel genetically engineered mouse strain, which carries a ?misfolding? mutation in the mouse carboxypeptidase A1 (Cpa1) gene. We will study how in this strain an alcohol diet affects spontaneous pancreatic damage, ER stress markers, cell death pathways and pathological responses in experimentally induced acute pancreatitis.

Public Health Relevance

The current grant proposal investigates how inborn genetic mutations in digestive enzymes can promote the development of alcoholic pancreatitis, a progressive inflammatory disease of the pancreas associated with chronic alcoholism. Results from this study can advance innovation towards novel diagnostic and therapeutic interventions in alcoholic pancreatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA026456-02
Application #
9647408
Study Section
National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
Program Officer
Gao, Peter
Project Start
2018-02-15
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston University
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118