Analysis of calcitonin receptor binding and function

受体是构成我们身体的细胞之间传递信号的基本媒介。因此，受体的调节在我们治疗疾病的能力中形成了一个关键目标。受体中最大的一类是G蛋白偶联受体（gpcr）超家族，它通过一种叫做G蛋白的蛋白质在细胞内传递信号。gpcr构成了人类全部基因库的1%到5%。一组gpcr为在体内循环的小蛋白质分子提供目标。其中一种循环分子是降钙素，这是一种肽，在维持体内循环钙水平方面起着重要作用，这对骨骼的适当维护至关重要。由于这种作用，降钙素是治疗骨质疏松症和佩吉特病等骨病的重要临床工具。由于降钙素及其受体（以及其他相关受体）的分子性质具有广泛而复杂的相互作用机制，我们对降钙素如何与其受体结合以向靶细胞发出信号的明确信息很少。目前的项目利用了一种将降钙素与其受体永久连接的新方法，从而可以确定这两个成分是如何结合在一起的。此外，该项目将探索自然发生的遗传变异（基因型）的功能后果，并研究特定降钙素受体基因型的发生是否与骨质疏松症和肥胖症的疾病标志物相关。这一信息为理解这种受体和相关受体如何工作以及合理设计改进的治疗工具提供了重要的基础。

Receptors form a basic intermediary as the acceptor site for signals that are transmitted between the cells that make up our body. Modulation of receptors, therefore, forms a key target in our ability to treat disease. The largest class of receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit signals within a cell via proteins called G proteins. GPCRs form between 1 and 5% of the entire repertoire of human genes. One group of GPCRs provide the target for small protein molecules that cirulate through the body. One such circulating molecule is calcitonin, a peptide that plays an important role in maintaining circulating calcium levels in the body, which is essential for proper maintenance of the skeleton. As a consequence of this action, calcitonin is an important clinically used tool in the treatment of bone disease such as osteoporosis and Paget's disease. Due to the molecular nature of calcitonin and its receptors (and other related receptors) that have a broad, complex mechanism of interaction, we have very little definitive information on how calcitonin interfaces with its receptor to signal to target cells. The current project utilises a novel method of permanently linking calcitonin to its receptor, allowing identification of how the two components come together. Furthermore, the project will explore the functional consequence of naturally occuring genetic variation (genotype) and also examine whether the occurence of specific calcitonin receptor genotype is correlated with disease markers for osteoporosis and obesity. This information provides important fundamentals for understanding how this and related receptors work and the potential for rational design of improved theraupeutic tools.