Mechanisms of Vascular Dysfunction in Cirrhosis

DESCRIPTION (provided by applicant): This is a 5-year training plan for a mentored physician scientist in Gastroenterology and Hepatology. The Principal Investigator is a junior faculty member in the Division of Gastroenterology and Hepatology at University of Maryland School of Medicine (UMSOM). Drs. Thomas Pallone and Jean-Pierre Raufman will co-mentor the Pi's scientific training. Dr. Pallone (Professor, Departments of Medicine and Physiology) is a renowned leader in microcirculation. Dr. Raufman (Chief, Division of Gastroenterology and Hepatology) has expertise in bile acid signaling. An Advisory Committee of established scientists/mentors will provide scientific and career guidance. The UMSOM provides an ideal training environment for the Pi's academic career development. The combination of mentoring, didactic coursework, unwavering institutional support and commitment will maximize the Pi's ability to launch a productive scientific career. The proposed study focuses on elucidating the mechanisms of vascular dysfunction in cirrhosis. The preliminary data indicates that (i) conjugated bile acids (BA) induce vasodilation in rodent aortae; (ii) BA-mediated vasodilation is endothelium-dependent and nitric oxide (NO)-mediated; (iii) M3 muscarinic receptor inhibition and ablation attenuates BA- and acetylcholine-mediated vasodilation. Our central hypothesis is that cholinergic stimulation of vascular endothelial cells mediates vascular dysfunction and systemic vasodilation in cirrhosis. The Specific Aims are (1) To define the role of M3R-dependent signaling in bile acid-mediated vasodilation; (2) To establish that bile acid-mediated changes in small mesenteric arterial tone mimic changes in aortic vascular tone; (3) To determine the mechanism whereby M3R contributes to vascular dysfunction in a mouse model of cirrhosis. Portal hypertension is a major cause of morbidity and mortality in advanced liver disease and vascular dysfunction contributes significantly to the progression of portal hypertension in this setting. The proposed complementary in vitro and in vivo approaches will help (a) determine the importance of cholinergic stimulation in the development of NO-mediated stress in EC, (b) elucidate molecular mechanisms of BA- mediated vasodilation and (c) determine the impact of M3R knockdown on vascular dysfunction in the animal model of experimental cirrhosis. This line of investigation will fill critical gaps in understanding the mechanisms of vascular dysfunction in cirrhosis and identify molecules for therapeutic targeting.