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Stem Cells in Liver Regeneration: Fusion or Plasticity

肝脏再生中的干细胞：融合或可塑性

基本信息

批准号：
8545163
负责人：
BRYON E PETERSEN
金额：
$ 38.19万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8545163
关键词：
Address Affect Autologous Transplantation Behavior Binding Bone Marrow Bone Marrow Cells CSF3 gene CXCR4 Receptors Cell Proliferation Cell Therapy Cell Transplants Cell membrane Cell physiology Cells Complex Data Development Disease model Engraftment Ensure Genetic Glycogen Goals Health Hematopoietic System Hepatic Hepatocyte Hereditary Disease In Vitro Inborn Genetic Diseases JAK2 gene Knowledge Laboratories Liver Liver Regeneration Liver diseases MAP Kinase Gene MEKs Measurable Mediating Metabolic Methods Modeling Molecular Mus Natural regeneration Organ Organ Transplantation PI3K/AKT Partial Hepatectomy Pathway interactions Patients Phenotype Play Property Protein Isoforms Rattus Relative (related person)Research Rodent Role Schedule Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Small Interfering RNA Source Stem cells Stromal Cell-Derived Factor 1 System Technology Testing Therapeutic Tissues Transplantation base clinically relevant cytokine design experience in vivo injured liver function liver injury liver transplantation migration oval cell protein kinase C zeta receptor regenerative repaired research study response therapy development trafficking treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The liver has an enormous capacity to regenerate, as demonstrated by the 2/3 partial hepatectomy model in rodents. In addition, the liver has a stem cell compartment acting as a backup regenerative system. Activation of the stem cell compartment takes place when hepatocytes are functionally compromised, are unable to divide, or both. In stem cell-aided liver regeneration, progeny of the stem cells multiply in an amplification compartment composed of hepatic oval cells. Several studies have shown that bone marrow cells can differentiate into hepatocytes, and we have also shown that bone marrow (BM) cells are able to produce hepatic oval cells. The foremost questions are: what molecular mechanisms are involved in oval cell physiology, and can these pathways be manipulated to enhance their therapeutic value in treating liver disorders? The experiments described within this proposal are designed to address the above stated questions. We will pursue the following specific aims: Specific Aim 1: We hypothesize that activation of the JAK2 and MAPK signal transduction pathways by G-CSF interaction with G-CSF receptor on the cell membrane enhances both proliferation and migration of liver oval cells. Specific aim 2: We hypothesize that activation of the MEK and PI3K signal transduction pathways following SDF-1 binding to CXCR4 receptor on the cell membrane enhances both proliferation and migration of liver oval cells. Specific aim 3: We hypothesize that modulation of the oval cell phenotype by G-CSF and SDF-1 will positively affect engraftment and expansion of compensatory oval cells into mouse liver afflicted with a genetic disorder, resulting in a measurable enhancement of liver function. It is anticipated that the proposed studies will yield new and significant data about the mechanisms of governing the bone marrow contribution to liver regeneration and signals involved in oval cell activation, proliferation and differentiation.

描述（由申请人提供）：肝脏具有巨大的再生能力，如啮齿动物2/3部分肝切除模型所示。此外，肝脏有一个干细胞隔室作为后备再生系统。当肝细胞功能受损、不能分裂或两者兼而有之时，干细胞区室的激活发生。在干细胞辅助的肝再生中，干细胞的后代在由肝卵圆细胞组成的扩增区室中繁殖。几项研究表明，骨髓细胞可以分化为肝细胞，我们还表明，骨髓（BM）细胞能够产生肝卵圆细胞。最重要的问题是：卵圆细胞生理学中涉及哪些分子机制，这些途径能否被操纵以增强其在治疗肝脏疾病中的治疗价值？本提案中描述的实验旨在解决上述问题。我们将追求以下具体目标：具体目标1：我们假设通过G-CSF与细胞膜上的G-CSF受体相互作用激活JAK 2和MAPK信号转导途径，增强肝卵圆细胞的增殖和迁移。具体目标2：我们假设SDF-1与细胞膜上的CXCR 4受体结合后MEK和PI 3 K信号转导途径的激活增强了肝卵圆细胞的增殖和迁移。具体目标3：我们假设，通过G-CSF和SDF-1调节卵圆细胞表型将积极影响补偿性卵圆细胞在患有遗传疾病的小鼠肝脏中的植入和扩增，从而导致肝功能的可测量增强。预计拟议的研究将产生新的和重要的数据有关的机制，管理骨髓的贡献，肝再生和信号参与卵圆细胞活化，增殖和分化。