Human Hepatocyte Growth Factors

人肝细胞生长因子

• 批准号: 6619110
• 负责人: WALLACE LEE MCKEEHAN
• 金额: $ 28.81万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619110
• 关键词: apoptosis; biological signal transduction; cell growth regulation; cell type; cholesterol; fibroblast growth factor; gene targeting; growth factor receptors; heparan sulfate; hepatocellular carcinoma; hepatocyte growth factor; homeostasis; laboratory mouse; lipid metabolism; liver cells; liver metabolism; liver regeneration; neoplastic process; protein structure function; proteoglycan; receptor expression; recombinant DNA; steroid metabolism; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): Liver processes critical for maintenance of organism homeostasis are well-characterized, however, much less is known about the regulation of cellular and metabolic homeostasis within the liver. Understanding cellular and molecular mechanisms underlying response of the liver to not only acute, but also chronic insult, that upsets internal liver homeostasis is essential for design of strategies for prevention and treatment of progressive liver diseases as cirrhosis and hepatoma. The FGF signaling system comprised of activating FGF, transmembrane tyrosine kinase (FGFR) and heparan sulfate proteoglycan is solely an internal sensor of perturbation and consequent cell-to-cell communication within tissues, including the liver. The identification of FGFR4 as the hepatocyte FGFR isotype, the application of mouse genetics, the available complete genome sequence and new analytical tools in the last project period yielded unexpected results and set clear new directions for this continuation project on the role of the FGF family in liver homeostasis. The specificity of FGF21, a potential liver specific FGF of the current 23, for FGFR isoforms and heparan sulfate, its liver cell type of origin and role in liver homeostasis will be determined. Whether FGF1 and/or FGF2 ablation in mice impacts compensatory growth of liver, cholesterol/bile acid metabolism and response to CCI4 damage and hepatolobular restoration will also be determined and compared to FGF21. Whether chronic activity of FGFR4 affects cholesterol/bile acid metabolism and response to CCI4 damage and hepatolobular restoration will be determined, as well as the specificity of FGFR4 in hepatocyte context for control of cholesterol/bile acid metabolism, response to CCI4 damage and hepatolobular restoration. We will determine whether FGFR4 impacts hepatolobular restoration by control of remodeling matrix proteases and characterize the regulation of cyp7a and CYP2E1 by FGFR4 at the cellular and cyp7a at the transcriptional level in HepG2 cells. The relative roles of FGFR1 and FGFR2 on promotion and/or delay of development of hepatomas in mice will be determined and the potentially new mouse models for carcinogen-induced hepatoma and progression to malignancy validated. We will characterize a novel nucleocytosolic complex/pathway (LRPPRC) that potentially coordinates microtubular cytoskeleton and mitochondrial movements with chromosome remodeling and tumor-suppressing apoptosis (RASSF1), and determine whether it interfaces with FGFR signaling, Taken together, these results at the molecular, cellular and animal level exploiting the strengths of in vitro structure-function analysts and mouse genetics will clarify the roles of the FGF/FGFR pairs that act specifically in liver context to mediate homeostasis or underlie pathology. The results will provide new mouse models for both homeostasis of cholesterol/bile acid and xenobiotic metabolism, as well as liver cancer.

描述(申请人提供)：肝脏过程对维持机体内环境平衡至关重要，然而，对肝脏内细胞和代谢内环境平衡的调节知之甚少。了解肝脏对急性和慢性损伤的反应的细胞和分子机制对于设计预防和治疗进行性肝病(如肝硬变和肝癌)的策略至关重要。由激活的成纤维细胞生长因子、跨膜酪氨酸激酶(FGFR)和硫酸乙酰肝素蛋白多糖组成的成纤维细胞生长因子信号系统是包括肝脏在内的组织内干扰和随后的细胞间通讯的内部传感器。FGFR4作为肝细胞FGFR亚型的鉴定、小鼠遗传学的应用、可用的全基因组序列和新的分析工具在最后一个项目期间产生了意想不到的结果，并为这个关于成纤维细胞生长因子家族在肝脏动态平衡中的作用的继续项目设定了明确的新方向。FGF21是一种潜在的肝脏特异性成纤维细胞生长因子，其对FGFR异构体和硫酸肝素的特异性、其来源的肝细胞类型和在肝脏动态平衡中的作用将被确定。FGF1和/或FGF2消融是否影响小鼠肝脏的代偿性生长、胆固醇/胆汁酸代谢以及对CCI4损伤和肝小叶重建的反应也将被确定并与FGF21进行比较。FGFR4的慢性活性是否影响胆固醇/胆汁酸代谢以及对CCI4损伤和肝小叶重建的反应，以及FGFR4在肝细胞环境中控制胆固醇/胆汁酸代谢、对CCI4损伤的反应和肝小叶恢复的特异性将被确定。我们将确定FGFR4是否通过控制重塑基质蛋白来影响肝小叶重建，并在细胞水平和转录水平上研究FGFR4对cyp7a和cyp7a的调节。FGFR1和FGFR2在促进和/或延缓小鼠肝癌发展中的相对作用将被确定，并验证潜在的新的致癌物诱导的肝癌和恶性进展的小鼠模型。我们将描述一种新的核胞质复合体/通路(LRPPRC)，它潜在地协调微管细胞骨架和线粒体运动与染色体重塑和肿瘤抑制凋亡(RASSF1)，并确定它是否与FGFR信号相互作用，综合考虑，这些结果在分子、细胞和动物水平上利用体外结构功能分析家和小鼠遗传学的优势，将阐明在肝脏背景下特异性地作用于肝脏的成纤维细胞生长因子/FGFR对调节动态平衡或基础病理的作用。这一结果将为研究胆固醇/胆汁酸的动态平衡和异种代谢以及肝癌提供新的小鼠模型。