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HGF and Signaling Pathways in Hepatic Tissue Assembly

HGF 和肝组织组装中的信号通路

基本信息

批准号：
8657817
负责人：
GEORGE K MICHALOPOULOS
金额：
$ 28.54万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657817
关键词：
Acute Liver Failure Animals Apoptosis Apoptotic Automobile Driving Bile Acids Biliary Cell Death Cessation of life Clinical Epidermal Growth Factor Receptor Epithelial Cells ErbB Receptor Family Protein Event Failure Family Financial compensation Grant Hepatectomy Hepatic Tissue Hepatocyte Human Investigation Knowledge Lead Ligands Literature Liver Liver Failure Liver Regeneration Liver parenchyma Massive Hepatic Necrosis Mus Natural regeneration Necrosis Partial Hepatectomy Pathway interactions Prevention Proto-Oncogene Protein c-met Rattus Receptor Protein-Tyrosine Kinases Resected Role S Phase Scheme Serum-Free Culture Media Signal Pathway Signal Transduction System TNF gene TNFSF10 gene Therapeutic Therapeutic Intervention Transplantation Up-Regulation Ursidae Family base cytokine design hepatic necrosis human disease knock-down liver transplantation meetings member pro-apoptotic protein receptor receptor coupling regenerative research study transdifferentiation

项目摘要

PROJECT SUMMARY/ABSTRACT This is a revised renewal application for a grant, now in its 5th year, aiming to understand the role of HGF and signaling pathways in hepatic tissue assembly. Our recent studies have demonstrated that HGF and its receptor Met, as well as EGF receptor and the EGFR associated ligands) constitute the only two receptor tyrosine kinases capable of delivering a mitogenic signal to hepatocytes (in serum-free media and when administered to the whole animal, rat or mouse). We have also showed that HGF/Met and EGFR are the only two signaling systems capable of promoting transdifferentiation of hepatocytes to biliary epithelial cells in culture. These unique effects of HGF/Met and EGFR are highly significant. Many other receptor tyrosine kinases are expressed in hepatocytes and their ligands are capable of activating the cognate receptor, yet mitogenic signals are limited to HGF/Met and EGFR. We have recently applied short term knock down (KD) of either HGF/Met or EGFR by ShRNA and demonstrated that both have inhibitory effects on liver regeneration, that the one signal cannot compensate totally for the other, and that the effects are different in scope and complexity. KD of EGFR was followed by compensatory increases in other members of the ErbB family and upregulation of MET. In each instance, there was significant but not lethal activation of pro-apoptotic pathways. We further extend these studies in rats and performed a double KD of both HGF/Met and EGFR followed by partial hepatectomy (PHx). The result was complete liver failure, with massive apoptosis and necrosis of most hepatocytes and collapse of the hepatic parenchyma. This effect was not seen when double KD was performed without PHx. The proposed study will aim to determine the signals that lead to liver failure under the hypothesis that many cytokines involved in liver regeneration (e.g. TNF and TGFb1) can also function as agents that bring hepatocyte death and liver failure when the mitogenic signals of both EGFR and MET fail to function. In addition to the experimental studies, we will also analyze expression and status of activation of the above receptors as well cytokines capable of inducing hepatocyte death and liver failure in human liver material obtained from cases of fulminant hepatic necrosis.. Finally we will assess the importance of the compensatory mechanisms emerging after KD of EGFR and determine whether abrogation of these mechanisms is capable to also lead to liver failure by itself. The combination of these studies may allow us to understand the mechanisms that lead to massive hepatic necrosis as an aberrant dis-coordination of the early signals involved in liver regeneration and allow design of therapeutic interventions for prevention of massive hepatic necrosis based on rational mechanistic schemes.

项目总结/文摘

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy.

DOI：
10.1371/journal.pone.0059836
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Nejak-Bowen K;Orr A;Bowen WC Jr;Michalopoulos GK
通讯作者：
Michalopoulos GK

Gliotoxin-induced changes in rat liver regeneration after partial hepatectomy.

胶霉毒素诱导部分肝切除后大鼠肝脏再生的变化。

DOI：
10.1111/liv.12164
发表时间：
2013-08
期刊：
Liver international : official journal of the International Association for the Study of the Liver
影响因子：
0
作者：
Nejak-Bowen KN;Orr AV;Bowen WC Jr;Michalopoulos GK
通讯作者：
Michalopoulos GK

Phenotypic fidelity (or not?) of epithelial cells in the liver.

DOI：
10.1002/hep.25703
发表时间：
2012-06
期刊：
HEPATOLOGY
影响因子：
13.5
作者：
Michalopoulos, George K
通讯作者：
Michalopoulos, George K

Development of a chemically defined medium and discovery of new mitogenic growth factors for mouse hepatocytes: mitogenic effects of FGF1/2 and PDGF.

DOI：
10.1371/journal.pone.0095487
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Bowen WC;Michalopoulos AW;Orr A;Ding MQ;Stolz DB;Michalopoulos GK
通讯作者：
Michalopoulos GK

Role of PINCH and its partner tumor suppressor Rsu-1 in regulating liver size and tumorigenesis.

DOI：
10.1371/journal.pone.0074625
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Donthamsetty S;Bhave VS;Mars WM;Bowen WC;Orr A;Haynes MM;Wu C;Michalopoulos GK
通讯作者：
Michalopoulos GK