Mission Statement:
The common theme in the Laboratory of Physiologic Studies is the use of in vivo animal models of human pathological states relevant to alcohol use disorders.
The Section on Neuroendocrinology conducts studies on the biology of endogenous cannabinoids and their receptors. Work focuses on the role of the endocannabinoid system in the control of energy homeostasis, including energy intake and peripheral energy metabolism, and its role in cardiovascular regulation. The work on energy intake aims to explore the role of endocannabinoids in the neuroendocrine control of appetite, including the appetitive aspects of ethanol drinking behavior. Endocannabinoids are also involved in the regulation of peripheral metabolism, and research in this section was first to identify the liver as a primary target of the effect of endocannabinoids on lipid metabolism and steatosis, induced either by high-fat diets or chronic alcohol intake.
Other studies highlight the role of endocannabinoid in cardiovascular regulation, particularly the regulation of cardiac contractile function in hypertension, and in the hypotensive state associated with liver cirrhosis. Work in the Section has also uncovered a putative novel endothelial receptor for endocannabinoids that mediates vasodilation, and selective ligands for this receptor have been developed.
The primary interest of the Section on Liver Biology is the immunological aspects and molecular pathogenesis of liver diseases. There are two main directions: 1) the role of innate immunity in liver injury and repair, and 2) and the role of the STAT family of transcription factors in mediating cytokine-induced liver injury and repair.
Alcohol consumption, nonalcoholic steatohepatitis (NASH), and viral hepatitis are three major causes of chronic liver injury leading to liver fibrosis, cirrhosis, and liver cancer. Increasing evidence suggests that immune cells play an important role in the pathogenesis of liver disease. The liver predominantly expresses innate immunity through the involvement of innate immune cells, including macrophages (i.e., Kupffer cells), natural killer (NK) cells, and natural killer T (NKT) cells. These cells are important as the first line of defense against infection and are poised to quickly respond to potential attacks by any pathogen in the absence of antigen recognition. Interestingly, in liver injury and repair, innate immunity is activated. Hence, this laboratory is investigating the immunologic mechanisms of liver injury and repair, focusing on innate immunity in liver disorders such as fatty liver and liver fibrosis, as well as in liver regeneration.
Another focus is the role of signal transducer and activator of transcription 3 (STAT3), a cytokine-activated transcription factor, in liver pathology. The group uses several murine models to study the roles IL-6, IL-22 and STAT3 in the development and progression of fatty liver diseases, liver injury, and repair. They have identified the important role of IL-6 in protecting against liver injury in NASH, fatty liver transplantation, and T cell hepatitis. Currently, they are exploring the role of STAT3 in these models by using STAT3 conditional knock out mice. They are also interested in studying the roles of other members of the STAT family in the above disorders.
The Section on Oxidative Stress Tissue Injury examines the role of oxidative-nitrosative stress and consequent poly(ADP-ribose) polymerase (PARP) activation in various forms of cardio- vascular pathologies, including those that are induced by chronic alcohol intake or develop as a consequence of aging. The preferred approach is to use a combination of state-of-the-art in vivo methodologies to analyze hemodynamic functions in combination with cell and molecular biological methods to study the expression and function of cellular proteins involved in tissue injury and inflammation, or acting as anti-inflammatory, protective and tissue repair mechanisms. As an example for the latter, the role of endocannabinoids as anti-inflammatory mediators acting via CB2 cannabinoid receptors in peripheral tissues is analyzed in ischemia-reperfusion models of tissue injury.
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