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，一组代谢物传感gpcr引起了人们对代谢性疾病治疗的兴趣，包括肥胖和糖尿病。在这些疾病中，脂肪组织发生显著的重塑，导致组织力学特性的变化。尽管先前的研究已经证明许多gpcr的功能会被机械刺激改变，但对于脂肪中的这些机械变化如何影响代谢物gpcr的功能，我们知之甚少。该项目将使用先进的显微镜技术来首先定义代谢物gpcr的操作如何影响脂肪细胞的机械特性。然后，它将确定这些机械特性的变化如何改变受体的信号谱。最后，这些信息将用于设计用于药物筛选的新型细胞模型，以适当地解释代谢紊乱中发生的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.