Programming GPCR signalling within the endocytic network; mechanisms and therapeutic applications

细胞通过发送和回应化学信息来相互交流。协调这种交流对于身体每个器官的正常运作是必不可少的。这些信息包括光的光子、我们闻到的化学物质、我们吃的食物、钙等矿物质离子、激素和神经递质（大脑的化学信使）。当化学信息与细胞表面称为受体的特定蛋白质结合时，它们就会被接收，受体将信息传递到细胞内。我们的研究集中在一个叫做G蛋白偶联受体（gpcr）的受体家族。我们的基因编码了800多种不同的gpcr，这些gpcr能够对许多不同的信息做出反应。身体的每个器官都有许多不同的gpcr。重要的是，这些受体的功能在各种疾病和失调中被破坏，包括癌症、肥胖、糖尿病、失明、心脏病、抑郁症、帕金森病、复发性流产和早产，仅举几例。尽管许多处方药都以gpcr为靶点，但对特异性更强、副作用更小、活性更持久的新化合物的需求很大。开发这些新药需要深入了解控制这些受体活性的分子机制。一旦任何细胞接收到与gpcr结合的外部信息，激活的受体将传递特定的信号以引发适当的细胞反应。这个过程是由细胞严格控制的。一个重要的机制是将受体从细胞表面快速移除或运输到称为核内体的内部隔间，作为关闭这些信号的一种手段。然而，我们发现某些被募集到特化核内体的gpcr，我们称之为非常早期核内体（VEE），可以开启新的信号通路。因此，GPCRs产生的信号的持续时间和位置都创造了对细胞至关重要的模式，告诉细胞是否释放更多的化学物质，激活特定的基因，分裂，甚至死亡。如果这种信号模式被破坏或误导，就可能导致疾病。然而，我们的发现也提出了一种可能性，即可以开发药物来重新定向受体并改变其在细胞中的功能。该项目的目的是通过检查参与运输的分子和来自VEE的gpcr的信号解码来了解细胞如何控制受体活性。我们最近的研究还表明，在生殖和妊娠早期重要的GPCR的VEE （LH受体）的转运可能在子宫如何对妊娠早期胚胎产生的激素作出反应中起重要作用，并且这些途径可能在反复流产的妇女中发生改变。我们还将通过研究感知食物中碳水化合物的重要受体（FFA2受体）和体外受精、癌症和更年期的靶向受体（FSH受体）来评估该隔室对其他gpcr的作用。对于FSH和LH受体，我们将确定药物是否可以改变特定gpcr到VEE或其他内体室的运输，进而影响受体活性。这项工作的结果将帮助我们理解细胞如何交流的基本机制。由于gpcr是常见的药物靶点，详细了解gpcr是如何受VEE调节的，甚至可能为更有效地治疗涉及该受体超家族的许多疾病提供新的途径。

Cells communicate to each other by sending and responding to chemical messages. Coordinating this communication is essential for correct functioning of every organ in the body. These messages include photons of light, chemicals that we smell, the food that we eat, mineral ions such as calcium, hormones and neurotransmitters (chemical messengers of the brain). The chemical messages are received when they bind to specific proteins on the cell surface called receptors, which relay the message in to the cell. Our research is focussed on a family of receptors called G protein-coupled receptors (GPCRs). Our genes encode for more than 800 different kinds of GPCRs that are capable of responding to numerous different messages. Each organ in the body has many different GPCRs. Importantly, the function of these receptors is disrupted in various diseases and disorders, including cancer, obesity, diabetes, blindness, heart disease, depression, Parkinson's Disease, recurrent miscarriage and pre-term birth, to name but a few. Although many prescribed drugs target GPCRs, there is a high demand for new compounds that are more specific, have fewer side effects, and that are active for longer. Developing these new drugs requires an in-depth understanding of the molecular machinery that controls the activity these receptors.Once any cell receives external messages that bind to GPCRs, the activated receptors will relay specific signals to elicit an appropriate cellular response. This process is tightly controlled by the cell. One important mechanism is the rapid removal, or trafficking, of receptors from the cell surface in to interior compartments called endosomes, as a means of switching off these signals. However, we discovered that certain GPCRs recruited to specialized endosomes, which we termed very early endosomes (VEE), can switch on new signalling pathways. So, both duration and location of signals generated by GPCRs creates patterns that are critical for the cell, telling it whether to release more chemicals, activate particular genes, divide, or even die. If such signalling patterns are disrupted, or misdirected, they can lead to disease. However, our discovery also raises the possibility that drugs can be developed to redirect the receptor and change its function in a cell. The aim of this project is to understand how a cell controls receptor activity by examining the molecules involved in trafficking and signal decoding of GPCRs from the VEE. Our recent work also revealed that trafficking to the VEE of a GPCR important in reproduction and in early pregnancy (the LH receptor) may be important in how the uterus responds to hormones produced by the embryo in early pregnancy, and that these pathways may be altered in women suffering recurrent miscarriage. We will also assess the role of this compartment to other GPCRs by studying a receptor important in sensing carbohydrates in our food (the FFA2 receptor) and another that is targeted in IVF, cancer and menopause (the FSH receptor). For FSH and LH receptor we will determine whether drugs can alter the trafficking of specific GPCRs to the VEE or other endosomal compartments, and in turn impact on receptor activity. The outcome of this work will help us understand fundamental mechanisms of how cells communicate. As GPCRs are common drug targets, detailed knowledge of how GPCRs are regulated by the VEE may even provide new avenues for more effective treatments of a number of conditions that involve this superfamily of receptors.