Mechanisms of Vascular Dysfunction in Cirrhosis

肝硬化血管功能障碍的机制

基本信息

批准号：
8293282
负责人：
Sandeep Khurana
金额：
$ 13.69万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-28 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8293282
关键词：
Ablation Acetylcholine Advisory Committees Agonist Animals Aorta Ascites Attenuated Bacterial Translocation Bile Acids Blood Circulation Blood Plasma Volume Blood Pressure Blood Vessels Cholinergic Agonists Cirrhosis 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 Muscarinics 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

项目摘要

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）：这是一项为期5年的培训计划，为胃肠病学和肝病学医师科学家提供了5年的培训计划。首席研究员是马里兰大学医学院（UMSOM）的胃肠病学和肝病学系的初级教职员工。博士。托马斯·帕隆（Thomas Pallone）和让·皮埃尔·劳夫曼（Jean-Pierre Raufman）将共同授权PI的科学培训。 Pallone博士（医学和生理学系教授）是微循环的著名领导者。 Raufman博士（胃肠病学和肝病学首席）在胆汁酸信号传导方面具有专业知识。成熟的科学家/导师的咨询委员会将提供科学和职业指导。 UMSOM为PI的学术职业发展提供了理想的培训环境。指导，教学课程，坚定不移的机构支持和承诺的结合将最大程度地提高PI发起富有成效的科学职业的能力。拟议的研究重点是阐明肝硬化中血管功能障碍的机制。初步数据表明（i）共轭胆汁酸（BA）在啮齿动物主动脉中诱导血管舒张；（ii）BA介导的血管舒张是内皮依赖性和一氧化氮（NO）介导的；（iii）M3毒蕈碱受体抑制和消融会减轻BA-和乙酰胆碱介导的血管舒张。我们的中心假设是血管内皮细胞的胆碱能刺激介导肝硬化中的血管功能障碍和全身性血管舒张。具体目的是（1）定义M3R依赖性信号传导在胆汁酸介导的血管舒张中的作用；（2）确定胆汁酸介导的小肠系膜动脉张力的变化模仿主动脉血管张力的变化；（3）确定M3R在小鼠肝硬化模型中导致血管功能障碍的机制。门户高血压是晚期肝病中发病率和死亡率的主要原因，在这种情况下，血管功能障碍对门户高血压的进展显着贡献。所提出的互补体外和体内方法将有助于（a）确定胆碱能刺激在EC中无介导的压力发展中的重要性，（b）阐明BA-介导的血管舒张的分子机制，并确定（c）确定的影响在实验性肝硬化动物模型中，M3R敲低血管功能障碍。这一研究将填补关键的空白，以了解肝硬化中血管功能障碍的机制，并确定用于治疗靶向的分子。