Understanding and Controlling Protein Aggregation and Disease: Molecular Mechanisms in vitro and in vivo
了解和控制蛋白质聚集和疾病:体外和体内的分子机制
基本信息
- 批准号:1774723
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:英国
- 项目类别:Studentship
- 财政年份:2016
- 资助国家:英国
- 起止时间:2016 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
BackgroundDespite the increasing importance of amyloid diseases including Parkinson's and Alzheimer's in our ageing population, we lack fundamental knowledge about how and why protein aggregation causes disease. Such knowledge is needed to develop successful therapeutic strategies against these age-related diseases. ObjectivesIn this project we will focus on a newly identified variant of beta2-microglobulin (beta2m) that causes fatal systemic amyloidosis. We will determine how and why this mutant aggregates; generate and characterize a C.elegans beta2m-disease model and screen for small molecules able to prevent its aggregation. We will then determine the mechanism of action of the small molecules in preventing aggregation in vitro and test their efficacy in a living organism exploiting C.elegans as a powerful model system.NoveltyIn recent work we have devised a novel and powerful screen in E.coli to identify small molecules that prevent protein aggregation. We will use this for a recently identified amyloid disease using a library of repurposed small molecules provided by our collaborator Richard Foster (School of Chemistry), and screen their efficacy and potential to enhance proteostasis in an intact living animal.TimelinessCombined with the exploitation of C.elegans as a screen for efficacy of small molecule hits in a living organism, the project will not only provide excellent training for a PhD student but it will also result in new knowledge of both fundamental and translational importance.Experimental approachThe project combines biochemistry, protein chemistry, structural biology and biophysics with in vivo analyses and high-throughput screening methodologies using C.elegans. All methods and approaches needed are already well established in the applicants' laboratories. Hence the student will obtain excellent training in a wide variety of methods and will apply them to an exciting multidisciplinary project that is achievable within the 4 year tenure of this PhD.
尽管淀粉样蛋白疾病(包括帕金森病和阿尔茨海默病)在老龄化人口中的重要性日益增加,但我们缺乏关于蛋白质聚集如何以及为什么导致疾病的基本知识。这些知识对于制定针对这些与年龄有关的疾病的成功治疗策略是必要的。在这个项目中,我们将重点研究一种新发现的β -微球蛋白(β - 2m)变异,它会导致致命的系统性淀粉样变性。我们将确定这种突变如何以及为什么聚集;生成并表征秀丽隐杆线虫beta2m疾病模型,并筛选能够阻止其聚集的小分子。然后,我们将确定小分子在体外防止聚集的作用机制,并利用秀丽隐杆线虫作为一个强大的模型系统,在活体中测试它们的功效。在最近的工作中,我们在大肠杆菌中设计了一种新颖而强大的筛选方法来识别阻止蛋白质聚集的小分子。我们将使用我们的合作者Richard Foster(化学学院)提供的重新定位的小分子文库,将其用于最近发现的淀粉样蛋白疾病,并筛选它们在完整活体动物中增强蛋白质静止的功效和潜力。结合利用秀丽隐杆线虫作为筛选小分子撞击生物体的效果,该项目不仅将为博士生提供良好的培训,而且还将产生具有基础和转化重要性的新知识。实验方法:本项目结合了生物化学、蛋白质化学、结构生物学和生物物理学以及秀丽隐杆线虫的体内分析和高通量筛选方法。所需的所有方法和途径都已经在申请人的实验室中得到了很好的建立。因此,学生将获得各种方法的优秀培训,并将其应用于一个令人兴奋的多学科项目,该项目将在该博士四年任期内实现。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A PQM-1-Mediated Response Triggers Transcellular Chaperone Signaling and Regulates Organismal Proteostasis.
- DOI:10.1016/j.celrep.2018.05.093
- 发表时间:2018-06-26
- 期刊:
- 影响因子:8.8
- 作者:O'Brien D;Jones LM;Good S;Miles J;Vijayabaskar MS;Aston R;Smith CE;Westhead DR;van Oosten-Hawle P
- 通讯作者:van Oosten-Hawle P
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其他文献
吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
- DOI:
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- 影响因子:0
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LiDAR Implementations for Autonomous Vehicle Applications
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
- DOI:
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- 影响因子:0
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Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
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- 影响因子:0
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