Identification and Characterization of Nutrient-Sensing Metabolite GPCRs

我的研究方向是分子内分泌学：细胞在分子水平上相互交流的方式。为了生存和执行预期的功能，邻近的细胞必须不断地感知环境条件和养分供应的变化，并通过细胞功能的微调变化来做出反应。营养状态信号，如蛋白质、脂肪、糖、代谢物和激素，通过激活细胞表面的特殊受体来协调这种动态的交流。G蛋白偶联受体超家族组成了800多个独特的细胞表面受体，能够检测这些不同的信号，以便不断调整以适应环境条件和需求。我和我的学生试图了解这些受体是如何在营养不足和营养过剩时控制细胞功能的。短期内，我们将重点放在这些受体的一个子集上，即所谓的代谢物GPCRs。我们问(1)这些受体对于细胞生存和代谢功能是必不可少的吗？(2)这些受体使用什么细胞机制来调节细胞功能？为了回答这些问题，我们使用受体缺失或添加技术，结合标准的分子生物学实验室分析，研究了多种激素分泌和敏感细胞类型(例如，肝、胰腺、脑)，以衡量不同代谢应激条件下的细胞健康和功能。使用这些方法，我们将回答一个生物学问题：细胞表面的GPCRs如何在环境压力下对细胞营养感知和生存做出贡献？这是细胞和整个动物生存的基本功能。通过比较和对比不同类型细胞中受体的使用，这些研究将提供对组织特定的营养检测机制的洞察，并将突出那些跨越多个组织并代表代谢调节基本过程的基本机制。

My research investigates molecular endocrinology: the ways in which cells communicate with one another on a molecular level. In order to survive and perform their intended functions, neighboring cells must continuously sense changes in environmental conditions and nutrient availability and respond through finely tuned alterations in cellular function. Nutrient status signals such as proteins, fats, sugars, metabolites, and hormones orchestrate this dynamic communication through activation of specialized receptors on the surface of cells. The G protein-coupled receptor (GPCR) superfamily constitutes greater than 800 unique cell-surface receptors capable of detecting these diverse signals in order to continuously adjust to environmental conditions and demand. My students and I seek to understand how these receptors control cell function during nutrient shortage and nutrient excess. In the short term, we are focusing on a subset of these receptors, the so-called metabolite GPCRs. We ask (1) are these receptors essential for cell survival and metabolic function? (2) What cellular mechanisms do these receptors use to modulate cell function? To answer these questions, we study multiple hormone-secreting and -sensitive cell types (e.g., liver, pancreas, brain) using receptor deletion or addition techniques, in combination with standard molecular biology lab analyses to measure cellular health and function under different metabolic stress conditions. Using these means, we will answer the biological question: How do cell surface GPCRs contribute to cellular nutrient sensing and survival during environmental stress? - a fundamental function for cells and whole animal survival. By comparing and contrasting receptor use in a variety of cell types, these studies will provide insight into tissue-specific mechanisms of nutrient detection and will highlight those essential mechanisms that span multiple tissues and represent fundamental processes in metabolic regulation.