Alpha-1 antitrypsin (AAT) deficiency

分析开发与筛选技术（ADST）旨在通过研究和开发创新的分析（测试）设计和化学文库筛选方法来推进治疗开发。构象疾病是由新合成蛋白质的错误折叠和促进蛋白质构象成熟、细胞内运输和蛋白质水解的系统的破坏引起的一组疾病。它们包括阿尔茨海默病、囊性纤维化、2型糖尿病和α -1抗胰蛋白酶（AAT）缺乏症。AAT是一种由父母通过基因传给孩子的遗传病。患有α -1的人接受了两个异常的α -1抗胰蛋白酶基因。后一种疾病是由肝细胞内质网中遗传突变AAT单体的错误折叠引起的。错误折叠的单体可以被蛋白酶体降解，但可以形成有毒的聚合物，通过自噬去除，并且已知应激的肝细胞会发生凋亡。AAT的分泌受损可导致成人严重的肺部疾病（功能丧失），而肝细胞中有毒聚合物的积累可导致任何年龄肝病的发展（毒性功能的获得）。重要的是，存在广泛的表型变异性，暗示遗传和/或环境修饰因子的作用。在Alpha-1项目（TAP）的资金支持下，与Alpha-1基金会科学顾问合作，我们设计了新的生物测定和技术，以支持AAT缺乏症的新治疗干预措施的发现和开发，这可能为治疗其他构象障碍提供一般策略。

Assay Development & Screening Technology (ADST) is designed to advance therapeutic development through research and development of innovative assay (test) designs and chemical library screening methods. Conformational diseases are a group of disorders caused by the misfolding of newly synthesized proteins and subversion of systems that facilitate protein conformational maturation, intracellular trafficking, and proteolysis. They include Alzheimers Disease, Cystic Fibrosis, Type 2 Diabetes, and Alpha-1 antitrypsin (AAT) deficiency. AAT is a genetic condition that is passed from parents to their children through their genes. People with Alpha-1 have received two abnormal alpha-1 antitrypsin genes. The latter disorder is caused by the misfolding of an inherited mutant AAT monomer in the endoplasmic reticulum of hepatocytes. The misfolded monomer is degraded by proteasomes, but can form toxic polymers that are removed by autophagy, and stressed hepatocytes are known to undergo apoptosis. The impaired secretion of AAT can result in serious lung disease in adults (loss of function), whereas the accumulation of toxic polymers in hepatocytes can lead to the development of liver disease at any age (gain of toxic function). Importantly there is extensive phenotypic variability, implicating roles for genetic and/or environmental modifiers. With financial support from The Alpha-1 Project (TAP) and in collaboration with Alpha-1 Foundation scientific advisors we have designed novel bioassays and technologies to support discovery and development of new therapeutic interventions for AAT deficiency, which may provide general strategies to treat additional conformational disorders.