Isoforms of PI 3-kinase as novel regulators of dsRNA-sensing and inflammation

PI 3-激酶亚型作为 dsRNA 传感和炎症的新型调节剂

• 批准号: BB/R017972/1
• 负责人: Bart Vanhaesebroeck
• 金额: $ 56.47万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR017972%2F1
• 关键词: Isoforms; PI; kinase; novel; regulators

This proposal seeks to investigate the roles of important regulators of fundamental processes inside mammalian cells, called phosphoinositide 3-kinases (or PI3Ks in short). One function of PI3Ks is to transmit signals from the outside to the inside of cells, and make the cells respond in appropriate ways. This process is called signal transduction. Another function is to remodel intracellular membranes to control a process called vesicular trafficking. Signal transduction and vesicular trafficking are interconnected, but much needs to be learned about how this works. Mammalian cells have eight family members of PI3K, divided in three subgroups. An important scientific question is to clarify the functions of the different PI3K family members and find out how they work. Thus far, scientists have mainly studied the group I PI3Ks and discovered specialised functions of the different family members, both in healthy tissue and in cancer, inflammation and diabetes. Drugs against group I PI3Ks are currently being tested in clinical trials in human cancer and allergy. The group III PI3K has been shown to be important for the distribution and processing of materials taken up by cells, as well as for a process called self-eating that helps to keep the cell clean and organized. At the moment, very little is known about the group II PI3Ks, especially about the processes they control in cells and whether they could be useful drug targets. In this proposal, we plan to explore novel functions of the group II PI3Ks, and to find out how they carry out these roles at the cellular level. In exploratory studies, we have identified an important signal transduction process in which vesicular traffic and the group II PI3K appear to be involved. This is the detection of so-called pathogen-associated molecular patterns (PAMPs) by Toll-like receptors. These serve as detectors of foreign invaders exhibiting such PAMPs, such as viruses and bacteria, and are crucial for our body's immune response. These receptors have also been implicated in how vaccines work and more recently, in cancer. Some of these discoveries have been made by studying mice in which PI3Ks have been inactivated, in order to uncover what these PI3Ks do in the living organism, and how they work. We believe that our proposed studies can clarify the mechanism by which group II PI3Ks control the interplay of endosomal traffic and the signalling by Toll-like receptors. This might, in future, provide the rationale to develop drugs that could interfere with these processes, to ultimately combat diseases where the immune system is deregulated, such as inflammatory conditions. This is a fundamental science proposal that will enhance our knowledge about basic biological phenomena. In the longer term, it is possible that this research may lead to a better understanding of disease processes and to the development of new medicines.

该提案旨在研究哺乳动物细胞内基本过程的重要调节剂的作用，称为磷酸肌醇3-激酶（简称PI 3 Ks）。 PI 3 Ks的功能之一是将信号从细胞外传递到细胞内，并使细胞以适当的方式做出反应。这个过程称为信号转导。另一个功能是重塑细胞内膜以控制称为囊泡运输的过程。信号转导和囊泡运输是相互关联的，但需要了解更多关于这是如何工作的。 哺乳动物细胞有八个PI 3 K家族成员，分为三个亚组。一个重要的科学问题是阐明不同PI 3 K家族成员的功能，并找出它们是如何工作的。 到目前为止，科学家们主要研究了I组PI 3 Ks，并发现了不同家族成员在健康组织和癌症，炎症和糖尿病中的特殊功能。针对I组PI 3 K的药物目前正在人类癌症和过敏的临床试验中进行测试。III族PI 3 K已被证明对细胞吸收的物质的分布和加工以及有助于保持细胞清洁和组织的自食过程非常重要。 目前，人们对II组PI 3 Ks知之甚少，特别是关于它们在细胞中控制的过程以及它们是否可以成为有用的药物靶点。在这项提案中，我们计划探索II组PI 3 Ks的新功能，并找出它们如何在细胞水平上发挥这些作用。在探索性研究中，我们已经确定了一个重要的信号转导过程中，囊泡交通和II组PI 3 K似乎参与。这是通过Toll样受体检测所谓的病原体相关分子模式（PAMP）。这些蛋白质可以检测到表现出这种PAMP的外来入侵者，如病毒和细菌，并且对我们身体的免疫反应至关重要。这些受体也与疫苗的工作方式有关，最近还与癌症有关。其中一些发现是通过研究PI 3 Ks失活的小鼠来获得的，目的是揭示这些PI 3 Ks在生物体中的作用以及它们如何工作。 我们相信，我们提出的研究可以阐明II组PI 3 Ks控制内体运输和Toll样受体信号转导相互作用的机制。这可能会在未来为开发可以干扰这些过程的药物提供理论基础，最终对抗免疫系统失调的疾病，如炎症。 这是一个基本的科学建议，将提高我们对基本生物现象的知识。从长远来看，这项研究可能会导致对疾病过程的更好理解和新药的开发。

项目成果

Local synthesis of the phosphatidylinositol-3,4-bisphosphate lipid drives focal adhesion turnover.

• DOI: 10.1016/j.devcel.2022.06.011
• 发表时间: 2022-07-25
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Posor Y;Kampyli C;Bilanges B;Ganguli S;Koch PA;Wallroth A;Morelli D;Jenkins M;Alliouachene S;Deltcheva E;Baum B;Haucke V;Vanhaesebroeck B
• 通讯作者: Vanhaesebroeck B

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

PI3K inhibitors are finally coming of age.

• DOI: 10.1038/s41573-021-00209-1
• 发表时间: 2021-10
• 期刊: Nature reviews. Drug discovery

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

Uninephrectomy and class II PI3K-C2ß inactivation synergistically protect against obesity, insulin resistance and liver steatosis in mice.

单肾切除术和 II 类 PI3K-C2α 灭活可协同保护小鼠免受肥胖、胰岛素抵抗和肝脏脂肪变性。

• DOI: 10.1111/ajt.16470
• 发表时间: 2021
• 期刊: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Alliouachene S