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（包括用于心脏病和多种其他疾病的β -受体阻滞剂）都是针对最大的细胞表面受体家族的，它们将细胞外的信号转化为细胞内的活性)，即7种跨膜受体（7TM-Rs）。这些药物靶向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严重的副作用。这可能部分是因为配体结合位点的靶向不够特异性，无法仅阻断所需的效果。这可能是由于受体的性质以及它在细胞内传递信号的方式。此外，现在已知不同的受体可以结合在一起，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形成信号的方式，以及是什么带来了信号的特异性。我们知道每个受体可以与多种信号通路耦合，并且特定的蛋白质可以调节受体的活性。我们怎样才能制造出更有针对性、副作用更小的药物呢？我想确定与新受体实体（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。一旦伴侣被发现，这将为研究人员提供新的治疗靶点，以补充当前的治疗方法，并可能减少药物的副作用。我的团队将使用我开发的一种新技术来识别独特和特定的异二聚体受体伙伴。这项新技术的开发是第一个允许特异性识别异二聚体受体伴侣的技术。目前药物的不良反应可能是由受体异二聚体引起的。了解这些受体的工作方式将有助于减少药物的副作用，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.