Pathobiology of the serpinopathies

丝氨酸病的病理学

• 批准号: G0500306/1
• 负责人: David Lomas
• 金额: $ 158.83万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0500306%2F1
• 关键词: Pathobiology; serpinopathies

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.

我们之前已经描述了一种新的疾病，我们称之为浆膜病。这些是由于一种名为丝氨酸蛋白酶抑制物或丝氨酸蛋白酶的蛋白质家族成员的突变所致。这些蛋白质的突变会导致它们改变大小和形状，导致组织沉积异常或功能丧失。血清病涵盖范围广泛的疾病，如肝硬变、血栓形成、血管水肿、肺气肿和最近的痴呆症。我们现在建议定义蛇针超家族成员的突变导致蛇纹病的机制。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是如何形成的，它们是如何被细胞处理的，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抗体，以便检测动物和人类组织中的异常蛋白质。最后，我们将定义人体如何从循环中清除这些不正常的蛋白质构象，以及它们如何刺激白细胞引起炎症和进一步的组织损伤。综上所述，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构成血清病的广泛疾病的策略。