Approximately 30,000,000 Americans have gallstones. This laboratory's long-term goal has been the evaluation of pathogenic mechanisms which may lead to new strategies to prevent cholesterol gallstones. The major pathogenic factors include 1) cholesterol supersaturated bile, 2) Diminished gallbladder motility, and 3) nucleation and growth of cholesterol monohydrate crystals. In recent years a number of pronucleating agents have been identified, but none account for the majority of whole bile pronucleating activity. Ongoing studies from this laboratory suggest that an 84 kDa nonmucin glycoprotein, which has recently been identified to be transferrin, may play an important role in e cholesterol crystal nucleation process. These observations along with the knowledge that cholesterol gallstones develop most commonly in women of childbearing age have led us to propose a new Central Hypothesis: Iron deficiency results in increased serum and biliary transferrin. increased biliary cholesterol secretion. enhanced cholesterol monohydrate crystal precipitation and cholesterol gallstone formation. Transferrin is a pro-nucleating agent, is concentrated in the vesicular fraction of bile, and is present, as is iron, in higher concentrations in the gallbladder bile of cholesterol gallstone than in control patients. However, the exact type and role of transferrin, and iron, in bile and the possible relationship between iron deficiency and gallstone formation need to be carefully examined. Therefore, we plan to pursue the following aims. The First Specific Aim is to further define the role of transferrin as a pronucleating agent and the relationship between serum and biliary transferrin. The Second Specific Aim is to determine the role of iron in gallstone pathogenesis. The Third Specific Aim is to compare levels of transferrin, iron, transferrin receptors, and hepatic enzymes in controls as well as cholesterol gallstone patient and animals. The Fourth Specific Aim is to determine the presence and site of transferrin and iron in cholesterol gallstones. The Fifth Specific Aim is to define the relationship between iron deficiency, biliary transferrin, an cholesterol gallstone formation. A series of human and prairie dog studies should confirm the proposed link between iron deficiency, biliary transferrin and cholesterol gallstones.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Surgery and Bioengineering Study Section (SB)
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Serrano, Jose
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Medical College of Wisconsin
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Parikh, Janak Atul; Beane, Joal D; Kilbane, E Molly et al. (2014) Is American College of Surgeons NSQIP organ space infection a surrogate for pancreatic fistula? J Am Coll Surg 219:1111-6
Mathur, Abhishek; Al-Azzawi, Hayder H; Lu, Debao et al. (2008) Steatocholecystitis: the influence of obesity and dietary carbohydrates. J Surg Res 147:290-7
Graewin, Shannon J; Kiely, James M; Lu, Debao et al. (2008) Leptin regulates gallbladder genes related to gallstone pathogenesis in leptin-deficient mice. J Am Coll Surg 206:503-10
Al-Azzawi, Hayder H; Nakeeb, Attila; Saxena, Romil et al. (2007) Cholecystosteatosis: an explanation for increased cholecystectomy rates. J Gastrointest Surg 11:835-42;discussion 842-3
Mathur, Abhishek; Megan, Marine; Al-Azzawi, Hayder H et al. (2007) High dietary carbohydrates decrease gallbladder volume and enhance cholesterol crystal formation. Surgery 141:654-9
Mathur, Abhishek; Walker, Julia J; Al-Azzawi, Hayder H et al. (2007) Ezetimibe ameliorates cholecystosteatosis. Surgery 142:228-33
Graewin, Shannon J; Kiely, James M; Svatek, Carol L et al. (2006) Ciliary neurotrophic factor restores gallbladder contractility in leptin-resistant obese diabetic mice. J Surg Res 130:146-51
Nakeeb, Attila; Comuzzie, Anthony G; Al-Azzawi, Hayder et al. (2006) Insulin resistance causes human gallbladder dysmotility. J Gastrointest Surg 10:940-8; discussion 948-9
Al-Azzawi, Hayder H; Mathur, Abhishek; Lu, Debao et al. (2006) Pioglitazone increases gallbladder volume in insulin-resistant obese mice. J Surg Res 136:192-7
Goldblatt, Matthew I; Swartz-Basile, Deborah A; Al-Azzawi, Hayder H et al. (2006) Nonalcoholic Fatty gallbladder disease: the influence of diet in lean and obese mice. J Gastrointest Surg 10:193-201

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