Alpha-1 antitrypsin (AAT) deficiency

检测开发和筛选技术(ADST)旨在通过研究和开发创新的检测(测试)设计和化学库筛选方法来推动治疗开发。构象疾病是由新合成的蛋白质错误折叠和促进蛋白质构象成熟、细胞内转运和蛋白质降解的系统被颠覆而引起的一组疾病。这些疾病包括阿尔茨海默病、囊性纤维化、2型糖尿病和阿尔法-1抗胰蛋白酶(AAT)缺乏症。AAT是一种遗传疾病，通过父母的基因遗传给他们的孩子。携带Alpha-1基因的人收到了两个异常的Alpha-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的AAT单体的错误折叠引起的。错误折叠的单体可被蛋白酶体降解，但可形成有毒的聚合物，可通过自噬移除，而应激肝细胞已知会发生凋亡。AAT的分泌受损可导致成人的严重肺部疾病(功能丧失)，而肝细胞中有毒聚合物的积聚可导致任何年龄的肝病(毒性功能的获得)。重要的是，有广泛的表型变异，暗示了遗传和/或环境修饰物的作用。在Alpha-1项目(TAP)的资金支持下，并与Alpha-1基金会的科学顾问合作，我们设计了新的生物测定和技术，以支持发现和开发新的AAT缺乏症治疗干预措施，这可能提供治疗其他构象障碍的一般策略。

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.