Exploiting metabolite GPCR mechanotransduction to find new treatments for metabolic disorders

GPCR是最大的膜蛋白家族，也是最成功的药物靶点。最近，一组代谢物感测GPCR在包括肥胖症和糖尿病的代谢紊乱的治疗中引起了兴趣。在这些疾病中，发生脂肪组织的显著重塑，导致组织的机械性质的变化。虽然以前的工作已经表明，许多GPCR的功能被机械刺激改变，很少有人知道这些机械变化脂肪影响代谢物GPCR的功能。该项目将使用先进的显微镜技术，首先确定代谢物GPCR的操作如何影响脂肪细胞的机械性能。然后，它将确定这些机械特性的变化如何改变受体的信号特征。最后，这些信息将用于设计新的细胞模型，用于药物筛选，以适当地解释代谢紊乱中脂肪组织机械特性的变化。

GPCRs are the largest family of membrane proteins and most successful drug targets. Recently a group of metabolite sensing GPCRs has attracted interest in the treatment of metabolic disorders, including obesity and diabetes. In these disorders significant remodeling of adipose tissue occurs, leading to changes in the mechanical properties of the tissue. Although previous work has demonstrated that the function of many GPCRs is altered by mechanical stimuli, very little is known about how these mechanical changes in adipose affect the function of metabolite GPCRs. This project will use advanced microscopy techniques to first define how manipulation of metabolite GPCRs affects the mechanical properties of adipocytes. It will then establish how these changes in mechanical properties alter the signaling profiles of the receptors. Finally, this information will be used to engineer novel cell models for drug screening that properly account for changes in the mechanical properties of adipose tissue that occur in metabolic disorders.