PATHOPHYSIOLOGY AND TREATMENT OF DISORDERS IN THE DISTAL

远端疾病的病理生理学和治疗

• 批准号: 6687316
• 负责人: Markus Grompe
• 金额: $ 29.09万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2005-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687316
• 关键词: antioxidants; carbon carbon hydrolase; carcinogenesis; carcinogenesis inhibitor; cell line; cell transplantation; clinical research; disease /disorder model; enzyme deficiency; gene mutation; gene therapy; genetically modified animals; hepatocellular carcinoma; inborn aminoacid metabolism disorder; laboratory mouse; liver metabolism; molecular oncology; nonhuman therapy evaluation; pathologic process; phenylacetates; tyrosinemias

DESCRIPTION (Copied from Applicant Abstract): Homogentisic acid dioxygenase (HGD), maleylacetoacetate isomerase (MAI) and fumarylacetoacetate hydrolase (FAH) sequentially catalyze the terminal degradation of tyrosine into Krebs cycle intermediates. Deficiency of HGD causes the human disorder alkaptonuria, (AKU) deficiency of FAH causes tyrosinemia type I (HT1) and the phenotype of MAI deficiency in man is unknown. HT1 is characterized by severe liver dysfunction, renal tubular damage and finally liver cancer. Previously we have generated a murine model of HT 1 and shown that the drug NTBC can prevent the neonatal lethality and liver dysfunction of FAH deficient mice. We also demonstrated a strong selective growth advantage of FAH expressing cells in mutant liver. This in vivo selection resulted in a near complete repopulation of diseased liver with healthy tissue and raised the hope that human HT1 may be curable by gene therapy. To broaden our understanding of the pathophysiology and potential therapy of HT1we have now also established murine models of HGD and MAI deficiency. This application pertains to the use of murine models of enzyme deficiencies in tyrosine catabolism to explore the biology of novel strategies for liver and kidney gene therapy, to better understand the etiology of hepatic cancer in HT1 and dissect the pathophysiology of the diseases in this pathway.

描述（从申请人摘要复制）：均匀酸二氧酶 （HGD），甲基乙酸异构酶（MAI）和富马乙酸乙酸酯水解酶 （fah）依次催化酪氨酸的末端降解为克雷布斯 循环中间体。 HGD的缺乏会导致人类疾病烷烃， （Aku）FAH的缺乏引起I型酪氨酸血症（HT1）和表型 人类的Mai缺乏症是未知的。 HT1的特征是严重的肝脏 功能障碍，肾小管损伤和最后的肝癌。以前我们有 产生了HT 1的鼠模型，并表明药物NTBC可以防止 FAH缺乏小鼠的新生儿致死性和肝功能障碍。我们也是 证明了FAH表达细胞的强烈选择性增长优势 突变肝。这种体内选择导致接近完整的重新群 患有健康组织的患病肝脏，并提出了人类HT1可能是 可通过基因疗法治愈。扩大我们对病理生理学的理解 HT1我们的潜在疗法现在还建立了HGD的鼠模型 和Mai缺乏症。 该应用与使用酶缺陷的鼠模型有关 酪氨酸分解代谢，以探索肝脏新型策略的生物学和 肾脏基因疗法，以更好地了解HT1中肝癌的病因 并剖析该途径中疾病的病理生理学。