Pancreatic diseases represent a major, poorly treated health-care problem in the United States. Unfortunately, once established the devastating effects of severe acute pancreatitis or chronic pancreatitis cannot be reversed. We believe true advances in the treatment of pancreatic disease, as in other diseases, rest in the early identification of at-risk individuals and in the prevention or limitation of the disease. Thus, the goal of our program is to determine the genetic and molecular mechanisms that predispose individuals to recurrent acute pancreatitis and chronic pancreatitis and to identify therapeutic targets.
Our Aims are to identify new mutations in susceptibility genes (starting with our chromosome 12 locus), and define the modifier genes and environmental factors that alter phenotypic expression and progression of pancreatic disease through fibrosis, calcifications, diabetes and disabling pain patterns. This will be accomplished by complementary laboratory techniques and statistical analysis and facilitated by expanding and revisiting our valuable family genetic resources. This proposal complements the North American Pancreas Study 2 (NAPS2) grant, a genetic epidemiology study that determines the prevalence of major pancreatitis associated gene mutations in the United States. The NAPS2 focuses on NON-familial pancreatitis, whereas the current hereditary pancreatitis (HP) Study focuses on families. The interaction between these grants occurs through referral of families that are identified in the NAPS2 study to the HP Study, and the determining whether genes found in families in the HP Study are generally important in US populations. The HP and familial pancreatitis studies are especially important because of the statistical power of family studies and the ability to detect modifier genes in a uniform background of susceptibility factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK054709-05A1
Application #
6733188
Study Section
Special Emphasis Panel (ZRG1-GMA-3 (01))
Program Officer
Serrano, Jose
Project Start
1999-04-01
Project End
2008-11-30
Budget Start
2004-03-21
Budget End
2004-11-30
Support Year
5
Fiscal Year
2004
Total Cost
$267,119
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Whitcomb, David C (2015) Innovation and hard work: The 2015 George E. Palade Medal Award Lecture. Pancreatology 15:611-5
Mounzer, Rawad; Whitcomb, David C (2013) Genetics of acute and chronic pancreatitis. Curr Opin Gastroenterol 29:544-51
Whitcomb, David C (2013) Genetic risk factors for pancreatic disorders. Gastroenterology 144:1292-302
Larusch, J; Whitcomb, D C (2012) Genetics of pancreatitis with a focus on the pancreatic ducts. Minerva Gastroenterol Dietol 58:299-308
Whitcomb, David C; LaRusch, Jessica; Krasinskas, Alyssa M et al. (2012) Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet 44:1349-54
Solomon, Sheila; Whitcomb, David C (2012) Genetics of pancreatitis: an update for clinicians and genetic counselors. Curr Gastroenterol Rep 14:112-7
Whitcomb, David C (2012) What is personalized medicine and what should it replace? Nat Rev Gastroenterol Hepatol 9:418-24
Whitcomb, David C (2012) Genetics of alcoholic and nonalcoholic pancreatitis. Curr Opin Gastroenterol 28:501-6
LaRusch, Jessica; Barmada, M Michael; Solomon, Shiela et al. (2012) Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred. JOP 13:258-62
Schneider, Alexander; Larusch, Jessica; Sun, Xiumei et al. (2011) Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. Gastroenterology 140:162-71

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