Pathobiology of alpha-1-antitrypsin deficency and the serpinopathies

丝氨酸蛋白酶抑制剂或丝氨酸蛋白酶抑制剂是一类在控制人体内酶方面起重要作用的蛋白质。自然发生的突变导致蛋白质改变形状，并在合成细胞内积聚成聚合物链。这会导致细胞死亡，从而导致肝硬化（如果蛋白质在肝脏中积累）或痴呆（如果蛋白质在大脑中积累）。我们建议评估聚合物形成的机制及其对合成它们的细胞的影响。我们还建议确定我们已经确定的小分子的作用机制，这些小分子可以在试管中阻断聚合物的形成，并减少疾病细胞模型中突变蛋白的积累。我们已经证明，有利于聚合物形成的突变也有利于非活性潜伏构象的形成。我们建议开发针对蛇蛋白α -1-抗胰蛋白酶和神经蛇蛋白潜在构象的新的单克隆抗体，以便我们在生物组织中识别它们，从而评估它们在疾病中的作用。α -1-抗胰蛋白酶的聚合物在α -1-抗胰蛋白酶缺乏症患者的肺部自发形成，它们灭活α -1-抗胰蛋白酶作为蛋白酶抑制剂，并作为化学引诱剂将炎症细胞招募到肺部。我们将使用我们的α -1-抗胰蛋白酶聚合物抗体来开发一种新的检测方法来成像肺内的病理聚合物。这将为从肺中清除聚合物提供有用的信息，并可能为α -1抗胰蛋白酶缺乏症患者肺部疾病的进展提供有用的信息。

The serine proteinase inhibitors or serpins are a family of proteins that play an important role in controlling enzymes within the human body. Naturally occurring mutations cause the protein to change shape and accumulate as chains of polymers within the cell of synthesis. This causes cell death and hence either cirrhosis (if the protein accumulates within the liver) or dementia (if it accumulates within the brain). We propose to assess the mechanism by which polymers form and their effect on the cells in which they are synthesised. We also propose to determine the mechanism of action of small molecules that we have identified that can block polymer formation in the test tube and reduce the accumulation of mutant protein in a cell model of disease. We have shown that mutations that favour the formation of polymers also favour the formation of an inactive latent conformation. We propose to develop new monoclonal antibodies to the latent conformation of the serpins alpha-1-antitrypsin and neuroserpin so that we can identify them in biological tissues and so evaluate their role in disease. Polymers of alpha-1-antitrypsin form spontaneously within the lungs of individuals with alpha-1-antitrypsin deficiency where they inactivate alpha-1-antitrypsin as a proteinase inhibitor as well as acting as a chemoattractant to recruit inflammatory cells to the lung. We will use our antibody to polymers of alpha-1-antitrypsin to develop a new assay to image pathological polymers within the lung. This will provide useful information on the clearance of polymers from the lung and perhaps the progression of lung disease in individuals with alpha-1-antitrypsin deficiency.