Human Hepatocyte Growth Factors

描述（由申请人提供）：对维持生物体内稳态至关重要的肝脏过程已得到充分表征，然而，关于肝脏内细胞和代谢体内稳态的调节知之甚少。了解肝脏不仅对急性，而且对慢性损伤的反应的细胞和分子机制，扰乱内部肝脏稳态对于设计用于预防和治疗进行性肝病如肝硬化和肝癌的策略是至关重要的。FGF信号传导系统由活化FGF、跨膜酪氨酸激酶（FGFR）和硫酸乙酰肝素蛋白聚糖组成，仅是扰动和随后的组织（包括肝脏）内细胞间通讯的内部传感器。FGFR 4作为肝细胞FGFR同种型的鉴定、小鼠遗传学的应用、可用的完整基因组序列和最后一个项目期间的新分析工具产生了意想不到的结果，并为FGF家族在肝脏稳态中的作用的这个继续项目设定了明确的新方向。将确定FGF 21（当前23种潜在的肝特异性FGF）对FGFR亚型和硫酸乙酰肝素的特异性、其肝细胞来源类型和在肝稳态中的作用。还将确定小鼠中的FGF 1和/或FGF 2消融是否影响肝脏的代偿性生长、胆固醇/胆汁酸代谢以及对CCI 4损伤和肝小叶恢复的响应，并与FGF 21进行比较。将确定FGFR 4的慢性活性是否影响胆固醇/胆汁酸代谢和对CCl 4损伤和肝小叶恢复的响应，以及FGFR 4在肝细胞背景下控制胆固醇/胆汁酸代谢、对CCl 4损伤和肝小叶恢复的响应的特异性。我们将确定FGFR 4是否通过控制重塑基质蛋白酶影响肝小叶恢复，并在HepG 2细胞中表征FGFR 4在细胞水平和cyp 7a在转录水平对cyp 7a和CYP 2 E1的调节。将确定FGFR 1和FGFR 2在促进和/或延迟小鼠肝癌发展方面的相对作用，并验证致癌物诱导的肝癌和进展为恶性肿瘤的潜在新小鼠模型。我们将描述一种新的核胞质复合物/途径（LRPPRC），它可能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（RASSF 1），并确定它是否与FGFR信号传导相互作用。利用体外结构-功能分析和小鼠遗传学的优势，在细胞和动物水平上将阐明FGF/FGFR对在肝脏环境中特异性作用以介导体内平衡或成为病理基础。这些结果将为胆固醇/胆汁酸的稳态和异生物质代谢以及肝癌提供新的小鼠模型。

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.