Role of Platelet derived growth factor receptor-a in Liver Patho-biology

血小板衍生生长因子受体-a 在肝脏病理生物学中的作用

• 批准号: 8617091
• 负责人: Satdarshan Singh Monga
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617091
• 关键词: Address; Adult; Albumins; Alcohols; American; Animal Model; Area; Basic Science; Biology; Blocking Antibodies; Carbon Tetrachloride; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chronic; Cirrhosis; Clinical Research; Complement; Defect; Development; Disease; Disease Progression; Economic Burden; Embryo; Equilibrium; Exhibits; Fibrosis; Generations; Grant; Growth; Growth and Development function; Health; Hepatic; Hepatocyte; Homeostasis; Human; In Situ Nick-End Labeling; In Vitro; Investigation; Knockout Mice; Lead; Ligands; Ligation; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver Regeneration; Liver diseases; Malignant Neoplasms; Mediator of activation protein; Metabolic; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Natural regeneration; PDGFRA gene; PDGFRB gene; Partial Hepatectomy; Pathology; Patients; Phosphorylation; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor alpha Receptor; Portal Hypertension; Primary carcinoma of the liver cells; Process; Recommendation; Regulation; Reporting; Research; Role; Signal Transduction; Staging; Stress; Transgenic Mice; Translating; Treatment Efficacy; United States National Institutes of Health; Up-Regulation; Viral hepatitis; base; bile duct; chronic liver disease; hepatoma cell; in vivo; inhibitor/antagonist; liver cell proliferation; liver injury; mortality; mouse model; novel; overexpression; paracrine; public health relevance; regenerative; response; sham surgery; socioeconomics

DESCRIPTION (provided by applicant): Chronic liver disease is a common cause of morbidity in the U.S.A. with around 5.5 million Americans suffering from hepatic fibrosis and cirrhosis. Chronic liver injury can be the result of any number of insults alone or in combination, including alcohol, viral hepatitis, metabolic defect or others. Cirrhosis can be further complicated by liver failure, portal hypertension and development of hepatocellular cancer (HCC), making chronic liver disease as the 12th leading cause of mortality in the U.S.A and a major socio-economic burden. The NIH action plan for liver research, identifies areas such as understanding cellular and molecular processes of normal liver cell functioning; liver regeneration and development; and hepatic fibrosis; to make an overall impact on liver health. The present grant is focused on understanding the role of a lesser known molecule in hepatocyte biology, platelet derived growth factor receptor-alpha (PDGFR¿) based on some intriguing observations made over last several years. High expression and phosphorylation of PDGFR¿ was identified during early stages of liver development in mice. Specifically, hepatoblasts and immature hepatocytes displayed high expression at early hepatic developmental stages that coincide with ongoing cell proliferation and cell survival. Blocking PDGFR¿ in embryonic liver culture verified these effects thus warranting an in depth investigation. Similarly, we have identified a dramatic increase in PDGFR¿ temporally during liver regeneration after two-third or partial hepatectomy (PH) in mice. Lastly, PDGFR¿ upregulation was observed in hepatocytes during hepatic fibrosis in patients, and after bile duct ligation (BDL) in mice. In order to unequivocally address the role of PDGFR¿ in liver growth & development, we have generated several mouse models that will enable us to address the overarching hypothesis that 'PDGFR¿ is a critical mediator of hepatocyte proliferation and survival and aberrations in its regulation lead to significant disruption of liver homeostasis leading to disorders of hepatic growth including aberrant development, regeneration, fibrosis & cirrhosis'. We propose to investigate this hypothesis through three specific aims, which are distinct and employ balanced in vivo and in vitro approaches. In aim 1, we propose to investigate PDGFR¿ signaling in early liver development via comprehensive ontogenic analysis to address its role and regulation. These studies will be complemented by generation of conditional null mice that lack PDGFR¿ in hepatoblasts. In aim 2, we will study PDGFR¿ signaling during liver regeneration in partial hepatectomy model and then address the impact of PDGFR¿ overexpression and deletion in hepatocytes on regenerative response utilizing novel animal models generated in the lab. In aim 3, we will study PDGFR¿ signaling in hepatic fibrosis and cirrhosis in murine models of bile duct ligation and carbon tetrachloride administration. These studies will be complemented by examining the cellular and molecular basis of the disease process in absence or overexpression of PDGFR¿ in hepatocytes in novel transgenic mice in our lab and complemented by utilization of species-specific PDGFR¿ blocking antibodies to determine impact on disease progression in these models to address therapeutic efficacy. Thus, this highly significant proposal will unequivocally and comprehensively address the role and regulation of PDGFR¿ in liver health and disease.

描述（由适用提供）：在美国，慢性肝病是发病率的常见原因，约有550万美国人患有肝纤维化和肝硬化。慢性肝损伤可能是单独或组合任何损伤的结果，包括酒精，病毒肝炎，代谢缺陷或其他损伤。肝病可能会因肝脏而更加复杂 肝癌（HCC）的衰竭，门户高血压和发育，使慢性肝病成为美国死亡率的第12个主要原因和主要的社会经济伯宁。 NIH肝脏研究的行动计划确定了诸如了解正常肝细胞功能的细胞和分子过程之类的领域；肝脏再生和发育；和肝纤维化；对肝脏健康产生总体影响。目前的赠款集中在理解鲜为人知的分子在肝细胞生物学，血小板衍生的生长因子受体-Alpha（PDGFR®）中的作用，该作用是基于过去几年进行的一些有趣的观察结果。 PDGFR¿PDGFR¿在胚胎肝培养中的高表达和磷酸化验证了这些作用，因此警告了深入研究。同样，在小鼠中三分之二或部分肝切开术（pH）后，我们在肝脏再生过程中暂时确定了PDGFR。急剧增加。最后，患者肝纤维化期间和小鼠胆管连接（BDL）在肝细胞中观察到PDGFR？在肝细胞中观察到PDGFR？。为了明确解决 PDGFR¿ in live growth & development, we have generated several mouse models that will enable us to address the overarching hypothesis that 'PDGFR¿ is a critical mediator of hepatocyte proliferation and survival and aberrations in its regulation lead to significant disruption of liver homeostasis leading to disorders of hepatic growth including aberrant development, regeneration, fibrosis & cirrhosis'.我们建议通过三个特定目标研究这一假设，这些目标是不同的，员工在体内和体外方法平衡。在AIM 1中，我们建议通过全面的个体分析来研究早期肝发育中的PDGFR？以解决其作用和调节。这些研究将通过在AIM 2中缺乏PDGFR？的有条件无效小鼠来完成，我们将研究肝脏再生期间的PDGFR？在部分肝造马模型中的肝脏再生过程中，然后解决PDGFR？PDGFR？PDGFR？PDGFR？PDGFR？PDGFR？PDGFR？PDGFR？PDGFR？PDGFR？PDGFR？PDGFR？在肝细胞中使用该实验室中产生的新型动物模型对肝细胞对肝细胞的过度表达和缺失的影响。在AIM 3中，我们将研究胆管连接和四氯化碳的鼠模型中的肝纤维化和肝硬化中的PDGFR？。这些研究将通过检查我们实验室中新型转基因小鼠的肝细胞中疾病过程中疾病过程的细胞和分子基础，并通过利用规格特异性PDGFR？通过使用这些模型对疾病进展的影响来解决治疗性有效性的影响。这是这项非常重要的提议将明确，全面地解决PDGFR知识在肝脏健康和疾病中的作用和调节。