Analysis of calcitonin receptor binding and function

受体作为构成我们身体的细胞之间传递信号的受体位点，形成了一个基本的中介。因此，受体的调节形成了我们治疗疾病能力的关键目标。最大的一类受体是G蛋白偶联受体（GPCR）超家族，它通过称为G蛋白的蛋白质在细胞内传递信号。GPCR占整个人类基因库的1%至5%。一组GPCR为在体内循环的小蛋白质分子提供靶点。其中一种循环分子是降钙素，这是一种在维持体内循环钙水平方面发挥重要作用的肽，这对骨骼的适当维护至关重要。由于这种作用，降钙素是治疗骨疾病如骨质疏松症和佩吉特病的重要临床使用工具。由于降钙素及其受体（和其他相关受体）具有广泛复杂的相互作用机制的分子性质，我们对降钙素如何与其受体相互作用以向靶细胞发出信号的确切信息很少。目前的项目利用一种新的方法将降钙素与其受体永久连接，从而可以识别这两种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，并检查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。这些信息提供了重要的基础知识，了解这一点和相关受体的工作原理和改进的治疗工具的合理设计的潜力。

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.