LIVER REPOPULATION FOR LIVER INJURY AND GENE THERAPY

肝损伤的肝脏再生和基因治疗

• 批准号: 6802280
• 负责人: SANJEEV GUPTA
• 金额: $ 43万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-06-20 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802280
• 关键词: cell growth regulation; cell proliferation; cell transplantation; clinical research; extracellular matrix; gap junctions; gene therapy; genetically modified animals; histochemistry /cytochemistry; human fetus tissue; injury; laboratory mouse; laboratory rat; liver cells; liver circulation; liver disorder; liver failure; liver pharmacology; liver regeneration; liver transplantation; peptidyl dipeptidase; polymerase chain reaction

DESCRIPTION (provided by applicant): Our general hypothesis is that transplanted liver cells will survive and function in the context of a permissive microenvironment, best exemplified by the liver. A variety of interactions between microenvironmental factors, other types of liver cells, and soluble factors could regulate engraftment of transplanted cells in the liver. Also, cell therapy requires creation of an adequate mass of transplanted cells in the liver. To demonstrate whether transplanted cells can engraft and proliferate in specific disorders, studies in suitable animal models are necessary. Such studies need to include analysis of human cells as well as assays of stem/progenitor cells for establishing appropriate clinical strategies. Progress in our laboratory over the past several years has led to the development of working models of transplanted cell engraftment and proliferation in the liver. Several important mechanisms have been identified that regulate the entry of transplanted cells in the liver parenchyma and further determine whether transplanted cells will proliferate or not. Specific perturbations in the host liver that promote cell engraftment include analysis of cells in liver sinusoids, modulations in the liver microenvironment and aspects of the biological properties of transplanted cells themselves. Genotoxic injury in native hepatocytes that spare transplanted cells from injury appears to be highly effective in promoting transplanted cell proliferation. A major goal of our continuing studies in this area concerns development of novel mechanisms in liver repopulation. We propose a series of studies to further define cell engraftment in the normal and the diseased liver of animals. We will study the fate of human liver cells in immunodeficient mice to generate further animal models. We will determine whether transplanted cells will proliferate following novel ways to induce genotoxic injury in the liver of recipient animals prior to cell transplantation. We will use these principles to approach correction of metabolic and genetic disorders in animals by liver-directed cell therapy. Completion of our studies will provide new knowledge in the areas of liver repopulation, stem cell biology and cell therapy. Our studies will provide valuable preclinical information for eventual applications of cell therapy in people.

描述（由申请人提供）：我们的一般假设是，移植的肝细胞将在允许的微环境中存活并发挥作用，最好的例子是肝脏。微环境因素、其他类型的肝细胞和可溶性因子之间的多种相互作用可以调节移植细胞在肝脏中的植入。此外，细胞疗法需要在肝脏中产生足够量的移植细胞。为了证明移植细胞是否可以在特定疾病中植入和增殖，有必要在合适的动物模型中进行研究。此类研究需要包括人类细胞分析以及干细胞/祖细胞分析，以建立适当的临床策略。我们实验室在过去几年中取得的进展导致了移植细胞在肝脏中的植入和增殖工作模型的开发。已经确定了几种重要的机制来调节移植细胞进入肝实质并进一步确定移植细胞是否会增殖。宿主肝脏中促进细胞植入的特定扰动包括对肝窦中细胞的分析、肝脏微环境的调节以及移植细胞本身的生物学特性方面。天然肝细胞的基因毒性损伤使移植细胞免受损伤，这似乎对促进移植细胞增殖非常有效。我们在这一领域持续研究的一个主要目标涉及肝脏再生新机制的发展。我们提出了一系列研究来进一步确定细胞在动物正常和患病肝脏中的植入。我们将研究免疫缺陷小鼠中人类肝细胞的命运，以产生进一步的动物模型。我们将在细胞移植前通过新方法在受体动物的肝脏中诱导基因毒性损伤来确定移植的细胞是否会增殖。我们将利用这些原理通过肝脏定向细胞疗法来纠正动物的代谢和遗传疾病。我们的研究的完成将为肝脏再生、干细胞生物学和细胞治疗领域提供新的知识。我们的研究将为细胞疗法最终在人类中的应用提供有价值的临床前信息。