Validation of the Vps34 PI 3-kinase as a new potential drug target in insulin sensitization

验证 Vps34 PI 3-激酶作为胰岛素增敏的新潜在药物靶点

• 批准号: BB/M013278/1
• 负责人: Bart Vanhaesebroeck
• 金额: $ 15.7万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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: https://gtr.ukri.org/projects?ref=BB%2FM013278%2F1
• 关键词: Validation; Vps34; PI; kinase; new

This proposal aims to test the hypothesis that the Vps34 enzyme plays a role in metabolism. In our previous studies, using genetic approaches in the mouse and funded by the BBSRC, we have discovered that partial inactivation of Vps34 leads to improved glucose-tolerance and protection against the negative effects of a high fat diet. This suggests that Vps34 inhibitors could be useful in diseases such as diabetes. We now propose to test whether newly developed chemical blockers of Vps34 can induce the same effects as genetic inactivation of Vps34, in cell- and mouse-based models. This is a proof-of-concept project which, if the outcome is positive, can lay the foundations for Vps34 drug development and a translational programme of work.

该提案旨在验证Vps34酶在代谢中起作用的假设。在我们以前的研究中，使用遗传方法在小鼠中并由BBSRC资助，我们发现Vps34的部分失活导致葡萄糖耐受性改善，并保护免受高脂肪饮食的负面影响。这表明Vps34抑制剂可能对糖尿病等疾病有用。我们现在建议测试新开发的Vps34的化学阻断剂是否可以在基于细胞和小鼠的模型中诱导与Vps34的遗传失活相同的效果。这是一个概念验证项目，如果结果是积极的，可以为Vps34药物开发和转化工作计划奠定基础。

项目成果

PI3K in Stemness Regulation: From Development to Cancer

PI3K 在干细胞调控中的作用：从发育到癌症

• DOI: 10.20944/preprints201911.0170.v1
• 发表时间: 2019
• 作者: Madsen R

A dual role for the class III PI3K, Vps34, in platelet production and thrombus growth.

• DOI: 10.1182/blood-2017-04-781641
• 发表时间: 2017-11
• 期刊: Blood
• 影响因子: 20.3
• 作者: C. Valet;M. Levade;G. Chicanne;B. Bilanges;C. Cabou;J. Viaud;M. Gratacap;F. Gaits‐Iacovoni;B. Vanhaesebroeck;B. Payrastre;S. Severin

Vps34/PI3KC3 deletion in kidney proximal tubules impairs apical trafficking and blocks autophagic flux, causing a Fanconi-like syndrome and renal insufficiency.

• DOI: 10.1038/s41598-018-32389-z
• 发表时间: 2018-09-20
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Grieco G;Janssens V;Gaide Chevronnay HP;N'Kuli F;Van Der Smissen P;Wang T;Shan J;Vainio S;Bilanges B;Jouret F;Vanhaesebroeck B;Pierreux CE;Courtoy PJ
• 通讯作者: Courtoy PJ

Phosphoinositide lipids in primary cilia biology.

• DOI: 10.1042/bcj20200277
• 发表时间: 2020-09-30
• 期刊: The Biochemical journal
• 作者: Conduit SE;Vanhaesebroeck B
• 通讯作者: Vanhaesebroeck B

Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism.

• DOI: 10.1038/s41467-017-01969-4
• 发表时间: 2017-11-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bilanges B;Alliouachene S;Pearce W;Morelli D;Szabadkai G;Chung YL;Chicanne G;Valet C;Hill JM;Voshol PJ;Collinson L;Peddie C;Ali K;Ghazaly E;Rajeeve V;Trichas G;Srinivas S;Chaussade C;Salamon RS;Backer JM;Scudamore CL;Whitehead MA;Keaney EP;Murphy LO;Semple RK;Payrastre B;Tooze SA;Vanhaesebroeck B
• 通讯作者: Vanhaesebroeck B