DESCRIPTION (provided by applicant): Hemin upregulates heme oxygenates-1 (HO-1), the stress induced enzyme implicated in protection from a variety of injuries, while its related isoform HO-2 is constitutively expressed. The role of hemin or HO-1 in the pancreas and their potential modulation of pancreatic injury are unknown. In preliminary experiments we find that peritoneal cells isolated from hemin-treated mice home to the pancreas and protect from pancreatitis. Our central hypothesis is that direct or indirect hemin exposure protects mice from experimental acute pancreatitis. We propose to test this hypothesis using two specific aims: Aim #1. Determine if the hemin-associated protection from acute pancreatitis is mediated by HO-1. This aim will be addressed by using HO-1 heterozygous and wild type mice to compare their susceptibility to pancreatic injury produced by two established models of experimental pancreatitis. This aim also entails exposing peritoneal macrophages to siRNA directed towards HO-1 in order to test if HO-1 activation is important for macrophage protection from pancreatitis. Aim #2. Compare the effects of direct hemin, or indirect hemin-activated cell-based therapy, as potential modes of prevention or cure of experimental pancreatitis. This aim will be carried out by assessing the effect of hemin intravenous administration on HO-1 induction in peripheral blood subpopulations and in the pancreas. This aim also seeks to identify the specific cell subpopulation within peritoneal cells that imparts the protective effect towards pancreatitis, and to compare the potential therapeutic effects of hemin versus activated peritoneal cell administration after induction of pancreatitis. Acute pancreatitis can be severely debilitating, if not lethal disease in humans. Most therapies are supportive and target the hemodynamic effects of pancreatitis such as dehydration together with removal of precipitating factors that may include alcohol or biliary obstructing calculi. The significance of our proposal pertains to laying the foundation to a potential therapeutic for pancreatitis, and bringing to light the involvement of HO-1 or one of its down stream by-products (eg carbon monoxide, iron or biliverdin) in pancreatic disease which hitherto has not been appreciated.
|Effective start/end date||9/20/05 → 8/31/07|
- National Institutes of Health: $187,488.00
- National Institutes of Health: $160,000.00