Integration of lipid and protein kinase signalling in primary cilia biology

该提案将研究调节细胞基本过程的PI3 -激酶（简称pi3k）。我们的实验室在发现不同PI3K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成员的药物来治疗PI3K失调的人类疾病方面发挥了主导作用。针对PI3K家族成员的抑制剂，包括我们发现的PI3K家族成员，现在被批准用于治疗白血病和乳腺癌。我们的研究重点是所谓的I类PI3K家族成员，这些成员已经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PI3K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经常被忽视的细胞器，称为初级纤毛。这是一个小的天线状结构，从每个细胞伸出来感知环境，对发育和正常的成年细胞和组织功能很重要。最近的研究，包括我们在相关细胞条件下调查PI3K的初步实验，已经确定了这些蛋白在控制初级纤毛方面的新功能。I类pi3k产生的脂质（称为PIP3）定位于初级纤毛。然而，目前尚不清楚哪一类PI3K对这种PIP3是重要的，以及PI3K和PIP3如何控制纤毛功能。我们将使用我们已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PI3K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对药物/药物开发过程至关重要。过度生长的条件得不到很好的治疗，我们确定的疾病机制可能会显示现有的药物如何在这些条件下使用，但也会揭示新的药物靶点。

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.