Determinants of binding and activity of G-protein coupled receptors RXFP1 and RXFP2; the receptors for relaxin and INSL3

松弛素是一种荷尔蒙，长期以来一直被认为在怀孕和分娩过程中起着至关重要的作用。然而，它也被证明在肾脏、心脏和中枢神经系统的功能中有更广泛的参与。它目前正在与我们的商业合作伙伴BAS Medical进行临床试验，用于治疗充血性心力衰竭、宫颈成熟和先兆子痫。此外，松弛素作为一种具有深远治疗效果的抗纤维化药物显示出巨大的前景，因为纤维化是所有形式的进行性心血管和肾脏疾病以及阻塞性呼吸道疾病(哮喘)的标志，在发达国家，这些疾病总共导致了40%-50%的死亡。由于研究人员无法识别其受体，对松弛素发挥细胞效应的机制的研究一直受到限制。我们现在知道，松弛素通过一种新的G蛋白偶联受体(GPCR)-松弛素家族多肽受体(RXFP)RXFP1发挥作用，也将作用于相关的受体RXFP2。RXFP2受体实际上是一种激素的受体，与松弛素有相似之处，INSL3。了解RXFP受体的功能不仅是因为它在妊娠中的重要作用，而且是因为它的临床应用，这是至关重要的。在这方面，更好地了解松弛素和INSL3如何与它们的受体相互作用以及这些受体如何发挥作用是至关重要的。我们将继续我们以前成功的方法来研究松弛素和INSL3与这些受体的相互作用以及受体发挥作用的机制。所获得的知识将有助于设计更小、更有效和更具口服活性的松弛素和INSL3形式，用于未来的临床应用。这种多学科的方法将使我们能够充分发挥这种神秘激素的临床潜力。

Relaxin is a hormone which has long been known to have essential roles in pregnancy and birth. However it has also been demonstrated to have far broader involvement in the functioning of the kidney, heart and central nervous system. It is currently in clinical trials with our commercial partner BAS Medical for the treatment of congestive heart failure, cervical ripening and preeclampsia. Furthermore, relaxin shows enormous promise as an antifibrotic agent which has far-reaching therapeutic consequences since fibrosis is a hallmark of all forms of progressive cardiovascular and renal disease and obstructive airway disease (asthma), which collectively contribute to 40-50% of deaths in developed countries. Research into the mechanisms whereby relaxin exerts its cellular effects has been limited by the inability of researchers to identify its receptor. We now know that relaxin acts through a novel G-protein coupled receptor (GPCR) Relaxin Family Peptide Receptor (RXFP) RXFP1 and will also acts on a related receptor RXFP2. The RXFP2 receptor is actually the receptor for a hormone with similarities to relaxin, INSL3. It is essential that an appreciation of RXFP receptor function is obtained not only for its important actions in pregnancy, but also for its clinical applications. In this regard, improved understanding of how relaxin and INSL3 interact with their receptors and how these receptors function is essential. We will continue our previously successful approaches to study the interaction of relaxin and INSL3 with these receptors and the mechanisms by which the receptors function. The knowledge gained will aid in the design of smaller, more potent and orally active forms of relaxin and INSL3 for future clinical applications. This multi-disciplinary approach will allow us to fully maximise the clinical potential of this enigmatic hormone.