Integration of lipid and protein kinase signalling in primary cilia biology

脂质和蛋白激酶信号在初级纤毛生物学中的整合

• 批准号: BB/W007460/1
• 负责人: Bart Vanhaesebroeck
• 金额: $ 60.23万
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW007460%2F1
• 关键词: Integration; lipid; protein; kinase; signalling

This proposal will investigate PI 3-kinases (PI3Ks in short) that regulate fundamental processes in cells. Our laboratory has played a leading role in finding out the roles of the different PI3K family members in the body, how they work and how drugs against some of them can be developed to treat human disease in which PI3K is deregulated. Inhibitors against PI3K family members, including a PI3K family member we discovered, are now approved for the treatment of leukaemia and breast cancer.Our studies focus on the so-called class I PI3K family members which have been extensively studied and implicated in disease, including in cancer and overgrowth syndromes, which are a group of diseases where different body tissues become large and abnormal, often including the blood vessels. Despite extensive of research, key elements of PI3K biology are poorly understood, in part because we believe their function has not been investigated in the appropriate conditions and models. Our proposal focuses on a much-overlooked organelle in cells, called the primary cilium. This is a small antenna-like structure that projects out of each cell to sense the environment and is important for development and normal adult cell and tissue function.Recent studies including our preliminary experiments investigating PI3K in relevant cell conditions have identified a new function for these proteins in controlling the primary cilium. The lipid that class I PI3Ks produce (known as PIP3) localises to primary cilia. However, it remains unknown which class I PI3K(s) are important for this PIP3 and how PI3Ks and PIP3 control cilia function. We will investigate these fundamental biological questions using well-established primary cilia model systems in which we have previous experience, then explore if our findings relate to overgrowth syndromes and may help to treat this condition.We believe our findings have the potential to uncover insight into long-standing questions in cilia biology and help to understand how increased activity of PI3K contributes to disease, including overgrowth syndromes. Understanding the mechanistic basis of disease informs and is essential for the process of drug/medicine development. Overgrowth conditions are poorly treated and disease mechanisms we identify may show how already existing drugs can be used in these conditions but also reveal new drug targets for development.

本研究将探讨调节细胞基本过程的PI 3-激酶（简称PI 3 Ks）。我们的实验室在发现不同PI 3 K家族成员在体内的作用，它们如何工作以及如何开发针对其中一些的药物来治疗PI 3 K失调的人类疾病方面发挥了主导作用。针对PI 3 K家族成员的抑制剂，包括我们发现的一种PI 3 K家族成员，现在已被批准用于治疗白血病和乳腺癌。我们的研究集中在所谓的I类PI 3 K家族成员，这些成员已被广泛研究并与疾病有关，包括癌症和过度生长综合征，这是一组不同身体组织变大和异常的疾病，通常包括血管。尽管进行了广泛的研究，但对PI 3 K生物学的关键要素知之甚少，部分原因是我们认为它们的功能尚未在适当的条件和模型中进行研究。我们的建议集中在细胞中一个被忽视的细胞器，称为初级纤毛。这是一个小的触角状结构，伸出每个细胞来感知环境，对发育和正常的成体细胞和组织功能非常重要。最近的研究，包括我们在相关细胞条件下研究PI 3 K的初步实验，已经确定了这些蛋白质在控制初级纤毛中的新功能。I类PI 3 K产生的脂质（称为PIP 3）定位于初级纤毛。然而，仍然不知道哪种I类PI 3 K对于该PIP 3是重要的以及PI 3 K和PIP 3如何控制纤毛功能。我们将使用我们以前有经验的成熟的初级纤毛模型系统来研究这些基本的生物学问题，然后探索我们的发现是否与过度生长综合征有关，并可能有助于治疗这种疾病。我们相信我们的发现有可能揭示纤毛生物学中长期存在的问题，并有助于了解PI 3 K活性增加如何导致疾病，包括过度生长综合征。了解疾病的机制基础通知，是必不可少的药物/药物开发的过程。过度生长状况的治疗效果很差，我们发现的疾病机制可能会表明现有药物如何用于这些状况，但也揭示了新的药物开发靶点。