基本信息
浏览量:3
职业迁徙
个人简介
The process of polymerisation is not unique to α1-antitrypsin but occurs in other members of the serine protease inhibitor (serpin) superfamily. Mutants of α1-antichymotrypsin, antithrombin, C1-inhibitor and heparin co-factor II were described by my team, and by others, that form polymers in vitro and in vivo. This is associated with emphysema, thrombosis and angiodema respectively. Perhaps most striking was our description of this process in neuroserpin to form inclusions within neurones and an autosomal dominant dementia that we named familial encephalopathy with neuroserpin inclusion bodies or FENIB. In view of the common mechanism linking all these diseases we have grouped them together as a new class of disorder that we have termed the serpinopathies. We have used our understanding of the serpinopathies to provide insights into other conformational diseases such as Alzheimer's, Huntington's and Parkinson's disease and the prion encephalopathies. The recognition that point mutations in neuroserpin underlie the dementia FENIB led us to assess the role of this protein in the more common dementia associated with Alzheimer's disease. We were able to demonstrate that neuroserpin is present in the plaques of individuals with Alzheimer's disease, that it forms a one-to-one interaction with the Aβ peptide and that it reduces the toxicity of this peptide in vitro and in a Drosophila model of disease. Our Drosophila model of Alzheimer's disease showed striking neurodegeneration and we therefore used it for a genetic screen to identify modifiers of the toxicity mediated by the Aβ peptide. Our data show a clear role for oxidative stress in neurodegeneration. Moreover we have collaborated with Chris Dobson's group (Chemistry, Cambridge) to use this model to develop algorithms of peptide toxicity in vitro and in vivo.
Alpha-1-antitrypsin deficiency is the only genetic factor that is widely accepted to predispose to COPD. The identification of novel genetic factors will provide new insights into the pathobiology of this disease. I have therefore worked with Ed Silverman (Harvard) to establish the International COPD Genetics Network that was funded by GSK. This network was used to demonstrate independent familial aggregation of the airway and emphysema components of COPD and to assess candidate genes in association studies. It has recently been used in GWAS to identify SNPs in the nicotinic acetylcholine receptor, the hedgehog interacting protein (HHIP) and FAM13A as being associated with COPD.
研究兴趣
论文共 643 篇作者统计合作学者相似作者
按年份排序按引用量排序主题筛选期刊级别筛选合作者筛选合作机构筛选
时间
引用量
主题
期刊级别
合作者
合作机构
Methods in molecular biology (Clifton, N.J.) (2024): 41-55
Gastro Hep Advances (2024)
FEBS JOURNAL (2024)
ACTA PHYSIOLOGICA (2023): 9-9
引用0浏览0引用
0
0
HEPATOLOGYno. 5 (2023): E118-E118
引用0浏览0引用
0
0
引用6浏览0WOS引用
6
0
Britta Handyside,Lening Zhang,Katina Ngo,Ryan Murphy,Joseph Chen,Nicole Galicia,Olivia Gorostiza,Glenn Pacheco,Lin Xie, Donald Mackenzie, Heidi Jones,Brian Heglar,
引用0浏览0引用
0
0
加载更多
作者统计
合作学者
合作机构
D-Core
- 合作者
- 学生
- 导师
数据免责声明
页面数据均来自互联网公开来源、合作出版商和通过AI技术自动分析结果,我们不对页面数据的有效性、准确性、正确性、可靠性、完整性和及时性做出任何承诺和保证。若有疑问,可以通过电子邮件方式联系我们:report@aminer.cn