功能性消化不良（Functional dyspepsia, FD）是临床常见的一种功能性胃肠病，主要表现为上腹部区域的不适症状, 包括胃疼、烧心、餐后不适和胃部饱胀感等, 而没有器质性原因能解释这些症状。胃痛觉高敏感性是功能性消化不良的重要病理特征之一。近年的临床研究发现FD病人的胃十二指肠中存在低度炎症，提示了低度炎症是可能的致病原因。然而，目前为止没有研究直接证明低度炎症在胃痛觉高敏感性中的作用。这其中的主要原因之一是没有动物模型能重现胃十二指肠的低度炎症。因此，在此研究中我们的目的是在动物模型中重现胃十二指肠的低度炎症，并证明低度炎症与胃痛觉高敏感性的联系。我们建立了母子分离大鼠模型。在大鼠出生的第1-10天内每天进行2小时的母子分离，在第7-8周龄时进行试验。我们的实验结果表明，母子分离大鼠在胃扩张刺激中表现出了胃痛觉高敏感性，同时p-ERK 1/2 在脊髓T9-T10段表达升高。嗜酸性粒细胞的数量及活性在胃十二指肠中显著升高，重现了低度炎症。用地塞米松抑制嗜酸性粒细胞性低度炎症后，胃痛觉高敏感性也得到了抑制。我们的研究主要表明了幼小期母子分离压力可引起成年后的胃痛觉高敏感性和胃十二指肠嗜酸性粒细胞性低度炎症，证明了低度炎症是造成胃痛觉高敏感性的原因之一。因此，对于伴有胃十二指肠低度炎症的FD病人，抗炎治疗应会是缓解症状的有效手段之一。

Rapid development of genome modification strategies have greatly facilitated the application of engineered mice models in basic research. Here I will briefly introduce the development strategy of mice models in Gempharmatech and there application in revealing mechanism in metabolic disorders like insulin resistance. The two-subunit GTPase activating protein RalGAP was demonstrated to be a critical regulator of muscle insulin action by negatively regulating the activity of the small G protein RalA, but how this regulation response to insulin response and crosstalk with lipid metabolism in skeletal muscle remained ambiguous. Using a series of RalGAP-related mutation mice models, we demonstrated that Thr735-phosphorylation of the α1 subunit of RalGAP (RalGAPα1) in response to insulin promoted glucose and long chain fatty acids (LCFAs) uptake via promoting translocation of Glut4 and Cd36 in normal skeletal muscle in mice. A RalGAPα1 point mutation strain blocking its phosphorylation impaired insulin-stimulated muscle assimilation of glucose and LCFAs and caused metabolic syndrome in mice, while conditional abletion of RalGAPα1 in skeletal muscle improved postprandial intake of glucose and lipids. Together, these data indicated RalGAPα1 as a dual-purpose target, and revealed potential target for treatment of acquired insulin resistance.

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