Mechanisms of Vascular Dysfunction in Cirrhosis

肝硬化血管功能障碍的机制

• 批准号: 7806780
• 负责人: Sandeep Khurana
• 金额: $ 0.05万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-28 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806780
• 关键词: Ablation; Acetylcholine; Advisory Committees; Agonist; Animals; Aorta; Attenuated; Bacterial Translocation; Bile Acids; Blood Circulation; Blood Plasma Volume; Blood Pressure; Blood Vessels; Cholinergic Agonists; Cirrhosis; Clinical; Data; Development; Endothelial Cells; Endothelium; Environment; Experimental Animal Model; Experimental Models; Faculty; Functional disorder; Gastroenterology; Gene Silencing; Generations; Goals; Guanosine Triphosphate; Heart Rate; Hemorrhage; Hepatology; Hypotension; In Vitro; Investigation; Liver diseases; Maryland; Mediating; Mediator of activation protein; Medicine; Mentors; Mesenteric Arteries; Mesentery; Microcirculation; Microdissection; Molecular; Morbidity - disease rate; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M3 Receptor; Muscle relaxation phase; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxides; Patients; Pharmacological Treatment; Physicians; Physiology; Portal Hypertension; Principal Investigator; Rattus; Receptor Inhibition; Relaxation; Resistance; Rodent; Role; Scientist; Serum; Signal Transduction; Signaling Molecule; Slide; Smooth Muscle; Sodium; Stress; Telemetry; Testing; Training; Universities; Vascular Endothelial Cell; Vasodilation; Video Microscopy; Water; Wild Type Mouse; career; career development; cholinergic; effective therapy; hemodynamics; in vivo; inhibitor/antagonist; medical schools; member; mortality; mouse model; novel; professor; receptor-mediated signaling; therapeutic target

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.

描述（由申请人提供）：