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ErbB Signaling in Liver Ontogeny and Regeneration

肝脏个体发育和再生中的 ErbB 信号转导

基本信息

批准号：
7895278
负责人：
WILLIAM E RUSSELL
金额：
$ 5.22万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895278
关键词：
Adult Animals Artificial Liver Biological Process Biology Carcinogens Cell Line Cell Proliferation Cell Transplantation Cells Chemical Injury Chemicals Complex Data Development Differentiation and Growth Disseminated Malignant Neoplasm ERBB2 gene Epidermal Growth Factor Epidermal Growth Factor Receptor Excision Family member Gene Targeting Generations Genes Genetic Goals Grant Growth Growth Factor Hepatectomy Hepatic Mass Hepatocyte Hepatocyte Growth Factor Homologous Gene Hypertrophy In Vitro Knockout Mice Laboratories Ligands Liver Liver Regeneration Malignant Neoplasms Mediating Metabolic Mitogens Modeling Mus Natural regeneration Normal tissue morphology Pharmaceutical Preparations Phenotype Phosphorylation Play Protein Family Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Proteolytic Processing Proto-Oncogene Protein c-met Recruitment Activity Regulation Role Signal Transduction Signaling Molecule Stimulation of Cell Proliferation Stress System Testing Tissues Transducers Tyrosine Phosphorylation Tyrphostins Undifferentiated Wound Healing autocrine carcinogenesis cell motility combinatorial improved injured knock-down knockout animal meetings migration oval cell polypeptide receptor response restoration tumorigenesis

项目摘要

Our long-term goal is to understand the mechanisms that control the growth, differentiation, and regeneration of the liver. Epidermal growth factor (EGF) and its homologs are the most thoroughly studied growth factors in the control of liver growth, regeneration and carcinogenesis. However, the relationship of EGF to the liver is complex, since we now know that there are multiple EGF-like molecules and that they act through four different receptors, the ErbB proteins. Signaling by ErbB tyrosine kinases depends on not only which ligands are present, but also which combinations of receptors are recruited into signaling complexes. There are also negative regulators of ErbB signaling, such as tyrosine phosphatases and proteins, such as Ralt, that complex directly with the ErbB proteins. This analysis is also complicated by the role of other receptors that interact with the ErbB proteins, including c-met, the receptor for HGF. We and others have shown that c-met requires a functional EGF receptor to elicit its effects on motility and mitogenesis. This grant focuses on the role played by the ErbB receptors as regulators of growth and differentiation in the liver. We have created hepatocytespecific EGFr, ErbB2, and ErbB3 deficient mice by gene targeting, and have obtained liver-specific cMet gene deleted mice. The specific aims of this proposal are to: 1) To define the interactions among the ErbB proteins and c-met in the mitogenic signaling of the normal and regenerating liver; 2) To evaluate the central role of the ErbB proteins as signal tansducers of HGF. Progress toward these aims will improve our understanding of how EGF-like molecules signal in a normal tissue, how the liver differentiates into its adult functional form, and how these potent mitogens regulate the dramatic restoration of liver mass during regeneration. Liver regeneration is a paradigm for other conditions of normal or altered growth regulation, including tissue hypertrophy, wound healing, and cancer. In addition to elucidating the mechanisms of growth control in the liver, our studies may ultimately aid in the generation of mature hepatocytes from undifferentiated cells for transplantation and for the generation of artificial livers.

我们的长期目标是了解控制生长的机制，