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

这项提议旨在研究哺乳动物细胞内称为磷脂酰肌醇3-激酶(简称PI3K)的基本过程的重要调节因子的作用。PI3K的功能之一是将信号从细胞外部传递到细胞内部，并使细胞以适当的方式做出反应。这个过程被称为信号转导。另一个功能是重塑细胞内的膜，以控制一个称为囊泡运输的过程。信号转导和囊泡运输是相互关联的，但对其工作原理还需要了解很多。哺乳动物细胞有八个PI3K家族成员，分为三个亚组。一个重要的科学问题是澄清不同PI3K家族成员的功能，并找出他们是如何工作的。到目前为止，科学家们主要研究了I组PI3K，发现了不同家族成员在健康组织中以及在癌症、炎症和糖尿病中的特殊功能。针对I组PI3K的药物目前正在进行人类癌症和过敏的临床试验。第三组PI3K已被证明对细胞吸收的物质的分配和处理以及有助于保持细胞清洁和组织的自噬过程非常重要。目前，人们对第二组PI3K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，我们计划探索第二组PI3K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，囊泡交通和II组PI3K似乎参与了这一过程。这是通过Toll样受体检测所谓的病原体相关分子模式(PAMPs)。它们作为外来入侵者的探测器，表现出这种PAMP，如病毒和细菌，对我们身体的免疫反应至关重要。这些受体也与疫苗的作用方式有关，最近还与癌症有关。其中一些发现是通过研究PI3K被灭活的小鼠来实现的，目的是揭示这些PI3K在活体中的作用以及它们是如何发挥作用的。我们相信，我们提出的研究可以阐明II组PI3K控制内体交通和Toll样受体信号传递的相互作用的机制。这可能在未来为开发可能干扰这些过程的药物提供理论基础，以最终对抗免疫系统放松管制的疾病，如炎症条件。这是一项基础科学建议，将增强我们对基本生物现象的了解。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。

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.