PKA-RIIβ信号通路在下丘脑GABA能神经元参与调控瘦素敏感性的机制研究

PKA plays important roles in cell signal transduction as well as the regulation of energy balance and metabolic homeostasis. PKA comprised of RIIβ subunit is distributed in brain and adipocytes. We created the RIIβ knockout mice showing lean phenotype by 50% adiposity and 20% leptin level in serum comparing to wild type. Under the condition of the low serum leptin, the mice remain normal metabolic rate suggesting raised leptin sensitivity. We excluded the adiposity and found that deficiency of RIIβ in hypothalamic GABAergic neurons confers the lean phenotype, however,the mechanism is unknown. We speculate that PKA-RIIβ signaling might interact with leptin signaling, and deficiency of RIIβ might made leanness by affecting leptin signal pathway. In this project, we plan to study on the interaction between PKA-RIIβ signaling and leptin signaling in the hypothalamic GABAergic neurons, as well as the site where PKA-RIIβ intervenes in to regulates leptin signaling. With our newly developed genetically engineered mutants for enzymatic study and transcriptome technology, we will reveal the mechanism underlying PKA involved the elevated leptin sensitivity. This study will be helpful to understand the mechanism controlling the metabolism and advantageous to the new drug discovery targeted to enzyme, also will provide a new possible approach for the treatment of metabolic diseases and obesity.

PKA是重要细胞信号传导分子，在机体能量平衡与代谢稳态调控中发挥重要作用。含有RIIβ亚基的PKA分布在脑神经元和脂肪细胞。我们构建的RIIβ亚基敲除小鼠表型消瘦，全身脂肪含量为正常值50%，血清瘦素水平为正常值20%。在低瘦素情况下，小鼠保持正常代谢水平，提示升高的瘦素敏感性。我们排除了脂肪细胞，确定下丘脑GABA能神经元RIIβ亚基缺失导致消瘦，但机制不明。我们推测PKA-RIIβ信号与瘦素信号存在相互作用，RIIβ缺失使瘦素信号敏感度上调造成消瘦。本项目中，我们将深入研究下丘脑GABA能神经元PKA-RIIβ信号通路与瘦素信号通路之间的相互作用，探讨PKA-RIIβ信号参与瘦素信号调控的介入环节，并利用我们新研发的基因工程酶学技术和转录子组学技术，阐明PKA调控瘦素敏感性的分子机制。该研究有助于深入认识代谢调控的分子机理，有利于酶类为靶点的新药研究，为肥胖等代谢疾病的治疗提供新途径。

本项目立题，基于PKA是重要细胞信号传导分子，并在机体能量平衡与代谢稳态调控中发挥重要作用。而且，含有RIIβ亚基的PKA分布在脑神经元和脂肪细胞。在以往的研究中，我们构建了RIIβ亚基敲除小鼠，其表型消瘦，全身脂肪含量为正常值50%，血清瘦素水平为正常值20%；在低瘦素情况下，小鼠保持正常代谢水平，提示升高的瘦素敏感性。我们的前期实验，排除了脂肪细胞PKA对于以上表型的作用，而确定了下丘脑GABA能神经元RIIβ亚基缺失会导致消瘦，但深入机制并不明确。在此之后，经过理论研讨，我们推测PKA-RIIβ信号与瘦素信号存在相互作用，RIIβ缺失可能使瘦素信号敏感度上调，进而造成消瘦。因此，本项目中，我们研究了下丘脑GABA能神经元PKA-RIIβ信号通路与瘦素信号通路之间的相互作用，探讨了PKA-RIIβ信号参与瘦素信号调控的介入环节，并利用我们新研发的基因工程酶学技术和转录子组学技术，深入阐明PKA调控瘦素敏感性的分子机制。该研究有助于深入认识代谢调控的分子机理，有利于酶类为靶点的新药研究，为肥胖等代谢疾病的治疗提供新途径。

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