Pathobiology of the serpinopathies

我们以前描述了一类新的疾病，我们称之为丝氨酸蛋白酶抑制剂病。这些发生作为一个家庭的成员突变的蛋白质称为丝氨酸蛋白酶抑制剂或丝氨酸蛋白酶抑制剂。这些蛋白质中的突变导致它们改变大小和形状，伴随异常组织沉积或功能丧失。丝氨酸蛋白酶抑制剂病包括广泛的疾病谱，如肝硬化、血栓形成、血管性水肿、肺气肿和最近的痴呆。我们现在建议定义丝氨酸蛋白酶抑制剂超家族成员突变引起丝氨酸蛋白酶抑制剂病的机制。特别是，我们将使用蛋白质，细胞和苍蝇模型来定义异常蛋白质如何形成，它们如何被细胞处理以及它们如何导致细胞死亡。此外，我们还将开发神经丝氨酸蛋白酶抑制剂的抗体，以便我们可以检测动物和人体组织中的异常蛋白质。最后，我们将确定身体如何从循环中清除这些异常构象的蛋白质，以及它们如何刺激白色细胞引起炎症和进一步的组织损伤。总的来说，这一工作方案将为许多不同的情况提供新的见解。我们实验室的长期目标是制定治疗包括丝氨酸蛋白酶抑制剂病在内的各种疾病的策略。

We have previously described a new class of disease that we have called the serpinopathies. These occur as a result of mutations in members of a family of proteins called the serine protease inhibitors or serpins. Mutations in these proteins cause them to change size and shape with either aberrant tissue deposition or loss of function. The serpinopathies encompass a wide spectrum of disease that is as diverse as cirrhosis, thrombosis, angioedema, emphysema and more recently dementia. We now propose to define the mechanisms by which mutations in members of the serpin superfamily cause the serpinopathies. In particular, we will use protein, cell and fly models to define how the abnormal proteins form, how they are handled by cells and how they cause cell death. In addition we will develop antibodies to neuroserpin so that we can detect the abnormal protein in animal and human tissues. Finally, we will define how the body clears these abnormal conformations of protein from the circulation and how they can excite white cells to cause inflammation and further tissue damage. Taken together, this programme of work will provide new insights into many different conditions. It is the long-term aim of our laboratory to develop strategies to treat the wide range of diseases that comprise the serpinopathies.