Acquisition of a FRET-capable microscope for heterodimeric G protein coupled receptor studies

目前用于治疗的大多数药物(包括心脏病的β-受体阻滞剂和其他多种药物)针对的是最大的细胞表面受体家族(将细胞外的信号转化为细胞内的活动)，即七种跨膜受体(7TM-R)。这些药物针对的是内源性化合物与受体相互作用的部位。不幸的是，所有这些药物都会产生显著的副作用。这在一定程度上可能是因为配体结合位点的靶点不够具体，不足以阻止所需的效果。这可能是由于受体的性质以及它实际上是如何在细胞内传递信号的。此外，现在已经知道不同的受体可以结合在一起并形成一个新的受体实体。令人惊讶的是，很少有人关注这些受体的形成方式来允许信号传递，以及什么带来信号传递的特异性。我们知道每个受体可以耦合到多个信号通路，并且特定的蛋白质可以调节受体的活动。我们如何才能制造出更具体、副作用更少的药物？我想确定与新的受体实体(受体异二聚体)相关的蛋白质，并了解蛋白质伙伴如何调节细胞内传递的信号。一旦知道了合作伙伴，这将为研究人员提供新的治疗靶点，将补充现有的治疗方法，并可能减少药物的不良反应。我的团队将使用我开发的一项新技术来识别独特和特定的异二聚体受体伙伴。这项新开发的技术是第一批能够特异性识别异二聚体受体伙伴的技术之一。目前药物的副作用可能是由受体异二聚体诱导的。了解这些受体的工作方式将有助于减少药物的不良反应，并帮助研究人员开发更好的治疗方法。

Most of the drugs currently used as therapies (including beta-blockers in heart disease and multiple others) are directed against the largest family of cell surface receptors which transduce signals outside of the cell into activity inside the cell), the seven transmembrane receptors (7TM-Rs). These drugs target the site where endogenous compounds interact with the receptor. Unfortunately, all of these drugs produce significant side effects. This may be in part because the targetting of the ligand binding site is not specific enough to block only the desired effect. This is likely due to the nature of the receptor and how it actually transmits signals inside the cell. Also, it is now known that different receptors can associate together and form a new receptor entity.  Surprisingly, very little attention has been given to the way these receptors form to permit signalling and what brings specificity of signalling.We know that each receptor can be coupled to multiple signalling pathways and that specific proteins can regulate the activity of the receptor. How can we make drugs that are more specific and have less side effects? I want to identify the proteins that associate with the new receptor entities (receptor heterodimers) and understand how the protein partners can regulate the signals transmitted inside the cell. Once the partners are known, this will provide researchers new therapeutic targets that will complement current therapies, and possibly reduce drug adverse effects. My group will use a new technology I developped to identify unique and specific heterodimeric receptor partners. The new technique developped is among the first ones to allow specific identification of heterodimeric receptor partners.Adverse effects of current drugs are probably induced by receptor heterodimers. Understanding the way these receptors work will help reduce drug adverse effects and help researchers develop better therapies.