HEPATOPULMONARY INVESTIGATIVE GROUP

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 慢性肝病及其并发症导致显著的发病率和死亡率，并在美国排名前十位的死亡原因。一种独特的并发症是肝硬化综合征（HPS），其在8-15%的肝硬化患者中发现，并且当肺内微血管扩张导致低氧血症时产生。HPS没有有效的治疗方法。肝移植是唯一的治疗选择，尽管HPS患者的围手术期死亡率似乎高于无HPS的患者，特别是在严重时。尽管HPS的流行和 一旦出现HPS导致的中度低氧血症，UNOS政策将增加移植的优先级，关于流行病学，自然史，发病机制，治疗和移植疗效的基本问题和缺乏前瞻性数据仍然存在。这些问题和它的独特性质 这种疾病突出了发展具有特定经验和兴趣的肝移植中心网络来研究这种综合征的重要性。在HPS模型中的实验工作为探索特定的遗传多态性作为易感性的贡献者和定义是否pendrifylline改善气体交换异常提供了理论基础。该项目的主要目标是了解HPS的流行病学、自然史和发病机制，以最大限度地提高患者的预后， 开发有效的治疗方法。为实现这一目标，将实现以下具体目标。在目标1中，我们将建立一个具有晚期肝病、肝移植和肺血管疾病专业知识的学术中心联盟，通过a）开发组织基础设施，B）定义诊断标准，c）标准化评估和建立临床组织和标本采集来研究HPS。在目标2中，我们将利用该联盟研究HPS的临床结局、发病机制和治疗，方法是：a）启动前瞻性评价、数据和标本收集以及临床随访，B）确定特定候选基因的遗传多态性是否与HPS易感性相关，以及c）设计并启动一项开放标签的先导性试验， 重度HPS。从完成这些目标中获得的数据将用于设计和提交HPS调查组的RO-1申请。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic Iiver disease and its complications cause significant morbidity and mortality and rank among the top ten causes of death in the United States. One unique complication is the hepatopulmonary syndrome (HPS) which is found in 8-15% of patients with cirrhosis and results when intrapulmonary microvascular dilatation results in hypoxemia. There are no effective medical therapies for HPS. Liver transplantation is the sole treatment option, although peri-operative mortality appears higher in patients with HPS than in patients without HPS, particularly when severe. Despite the prevalence of HPS and the UNOS policy of increasing priority for transplantation once moderate hypoxemia due to HPS is present, fundamental questions and a lack of prospective data remain regarding epidemiology, natural history, pathogenesis, therapy and the efficacy of transplantation. These questions and the unique nature of this disorder highlight the importance of developing a network of liver transplantation centers with specific experience and interest to study this syndrome. Experimental work in HPS models provides a rationale for exploring specific genetic polymorphisms as contributors to susceptibility and for defining whether pentoxifylline ameliorates gas exchange abnormalities. The broad goal of this project is to understand the epidemiology, natural history, and pathogenesis of HPS in order to maximize patient outcomes and develop effective therapies. To accomplish this goal, the following specific aims will be undertaken. In Aim 1, we will establish an alliance of academic centers with expertise in advanced liver disease, liver transplantation and pulmonary vascular disease to study HPS by a) developing an organizational infrastructure, b) defining diagnostic criteria and, c) standardizing evaluation and establishing clinical tissue and specimen acquisition. In Aim 2, we will use the alliance to investigate clinical outcomes, pathogenesis and therapy of HPS by a) initiating prospective evaluation, data and specimen collection and clinical follow up, b) defining if genetic polymorphisms in specific candidate genes are associated with susceptibility to HPS and c) designing and initiating an open label pilot trial of pentoxifylline in severe HPS. The data obtained from completion of these aims will be used to design and submit an RO-1 application by the HPS Investigative Group.