Roles of enzymes of the dipeptidyl peptidase gene family in human liver

慢性肝病，特别是由自身免疫性疾病、酒精和乙型和丙型肝炎病毒感染引起的疾病，是导致我们社会疾病和死亡的主要原因。它们的特点是肝脏逐渐形成疤痕，最终导致肝功能衰竭，在许多情况下需要器官移植。每年有15,000名澳大利亚人感染丙型肝炎病毒，可能是终身感染。除非开发出更有效的治疗方法，否则这些感染中约有20%将在30年内进展为肝功能衰竭或肝癌。1.5亿人患有糖尿病，其中90%患有2型糖尿病。我们要求资助我们对一种极具前景的酶家族的研究，作为这些疾病的新疗法的目标。我们是国际公认的该酶家族和肝病方面的专家。这种酶家族的原型成员二肽基肽酶(DP)IV是治疗2型糖尿病的第三阶段临床试验中的新药的靶标。家族成员成纤维细胞激活蛋白(FAP)是新型抗癌药物的靶点，我们首先克隆了该家族的两种新酶DP8和DP9并申请了专利。我们的研究建议将导致确定FAP、DP8和-或DP9是否是新的肝病治疗药物的有价值的靶点，并通过更彻底地了解这些酶的活性和作用来促进此类治疗药物的开发。完成这个项目将极大地增加我们对这些酶及其在慢性肝损伤中的作用的理解。这项工作可能会导致开发专门的酶功能抑制剂，旨在减轻肝脏损伤。

Chronic liver diseases, particularly those caused by autoimmune disease, alcohol and Hepatitis B and C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. Each year 15,000 Australians become infected, probably for life, with hepatitis C virus. Unless more effective treatments are developed approximately 20% of these infections will progress to liver failure or liver cancer within 30 years. Diabetes afflicts 150 million people, and 90% have Type 2 diabetes. We request funding of our research on a family of enzymes highly prospective as targets for novel therapies for these diseases. We are internationally recognised experts on this enzyme family and on liver disease. The prototype member of this enzyme family, dipeptidyl peptidase (DP) IV, is being targeted by novel drugs that are in phase III clinical trials for Type 2 diabetes. Family member fibroblast activation protein (FAP) is targeted by novel anti-cancer drugs We were first to clone and lodge patent applications for two new enzymes of this family, DP8 and DP9. Our research proposal would lead to determination of whether FAP, DP8 and-or DP9 are valuable targets for novel liver disease therapeutics and facilitate generating the development of such therapeutics by a more thorough understanding of the activities and roles of these enzymes Completion of this project will greatly increase our understanding of these enzymes and their roles in chronic liver injury. This work can potentially lead to the development of specific inhibitors of enzyme function designed to relieve liver damage.