Human Hepatocyte Growth Factors

人肝细胞生长因子

• 批准号: 7024526
• 负责人: WALLACE LEE MCKEEHAN
• 金额: $ 28.13万
• 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/7024526
• 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（由申请人提供）：对维持生物体稳态至关重要的肝脏过程已经被很好地描述，然而，对肝脏内细胞和代谢稳态的调节知之甚少。了解肝脏对急性和慢性损伤反应的细胞和分子机制，破坏肝脏内部稳态，对于设计预防和治疗肝硬化和肝癌等进行性肝病的策略至关重要。FGF信号系统由激活FGF、跨膜酪氨酸激酶（FGFR）和硫酸肝素蛋白聚糖组成，仅是组织（包括肝脏）内部扰动和细胞间通讯的内部传感器。FGFR4作为肝细胞FGFR同型的鉴定，小鼠遗传学的应用，现有的全基因组序列和新的分析工具在上一个项目期间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继续项目设定了明确的新方向。FGF21（目前23种潜在的肝脏特异性FGF）对FGFR亚型和硫酸肝素的特异性、其肝细胞来源类型和在肝脏稳态中的作用将被确定。FGF1和/或FGF2消融是否会影响小鼠肝脏代偿生长、胆固醇/胆汁酸代谢、CCI4损伤反应和肝小叶恢复也将被确定并与FGF21进行比较。FGFR4的慢性活性是否影响胆固醇/胆汁酸代谢、对CCI4损伤和肝小叶恢复的反应，以及FGFR4在肝细胞背景下控制胆固醇/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酶影响肝小叶修复，并表征FGFR4在HepG2细胞中在细胞水平和cyp7a在转录水平上对cyp7a和CYP2E1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，并可能验证致癌物质诱导的肝癌和恶性进展的新小鼠模型。我们将描述一种新的核胞质复合体/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（RASSF1），并确定它是否与FGFR信号相结合。利用体外结构功能分析和小鼠遗传学的优势，细胞和动物水平将阐明FGF/FGFR对在肝脏环境中特异性起作用，介导体内平衡或潜在病理的作用。该结果将为胆固醇/胆汁酸稳态和外源代谢以及肝癌提供新的小鼠模型。

项目成果

Receptor phenotype underlies differential response of hepatocytes and nonparenchymal cells to heparin-binding fibroblast growth factor type 1 (aFGF) and type 2 (bFGF).

受体表型是肝细胞和非实质细胞对肝素结合成纤维细胞生长因子 1 型 (aFGF) 和 2 型 (bFGF) 差异反应的基础。

• DOI: 10.1007/bf02634135
• 发表时间: 1992
• 期刊: In vitro cellular & developmental biology : journal of the Tissue Culture Association
• 作者: Kan,M;Yan,GC;Xu,J;Nakahara,M;Hou,J
• 通讯作者: Hou,J

Fibronectin, not laminin, mediates heparin-dependent heparin-binding growth factor type I binding to substrata and stimulation of endothelial cell growth.

纤连蛋白（而不是层粘连蛋白）介导肝素依赖性肝素结合生长因子 I 型与基质的结合并刺激内皮细胞生长。

• DOI: 10.1007/bf02623692
• 发表时间: 1990
• 期刊: In vitro cellular & developmental biology : journal of the Tissue Culture Association
• 作者: Kan,M;Shi,EG
• 通讯作者: Shi,EG

Expression and immunochemical analysis of rat and human fibroblast growth factor receptor (flg) isoforms.

大鼠和人成纤维细胞生长因子受体 (flg) 亚型的表达和免疫化学分析。

• 发表时间: 1992
• 期刊: The Journal of biological chemistry
• 作者: Xu,J;Nakahara,M;Crabb,JW;Shi,E;Matuo,Y;Fraser,M;Kan,M;Hou,J;McKeehan,WL
• 通讯作者: McKeehan,WL

Direct analysis of growth factor requirements for isolated human fetal hepatocytes.

直接分析分离的人胎儿肝细胞的生长因子需求。

• DOI: 10.1007/bf02620987
• 发表时间: 1987
• 期刊: In vitro cellular & developmental biology : journal of the Tissue Culture Association
• 作者: Hoshi,H;Kan,M;McKeehan,WL
• 通讯作者: McKeehan,WL

Substitution of putative half-cystine residues in heparin-binding fibroblast growth factor receptors. Loss of binding activity in both two and three loop isoforms.

• DOI: 10.1016/s0021-9258(19)37115-7
• 发表时间: 1992-09
• 期刊: The Journal of biological chemistry
• 作者: J. Hou;M. Kan;F. Wang;J. Xu;M. Nakahara;G. McBride;K. Mckeehan;W. Mckeehan