Acute reciprocal regulation of adiponectin and leptin

该项目的研究计划重点是应用遗传学模式生物小鼠，在体内研究脂联素和瘦素的急性相互交叉调节机制。目的1“确定脂联素siganling是否以及如何通过AdipoR 1和AdipoR 2调节瘦素的产生”和目的2“确定瘦素信号是否以及如何通过LepRb调节脂联素的产生”被细分为发现和干预部分。发现部分：各种各样的优秀的新小鼠模型将使我能够研究AdipoR和LepR信号的时空解释。结合脂肪细胞特异性多西环素诱导的AdipoR双敲除小鼠模型和脂肪细胞特异性多西环素诱导的LepR敲除小鼠模型将使我能够反映相互作用的双方。干预部分：发现在脂肪细胞中通过各自的受体信号传导调节的最显著的靶标将通过已建立的腺相关病毒（AAV）基因转移技术来操纵。通过我的脂肪细胞选择性AAV靶向方法，可以迅速获得脂联素和瘦素交叉调节的机制见解。使用小分子抑制剂的替代方法将增加方法的多样性。目标3，“探索操纵肥胖症中脂联素/瘦素交叉调节的关键信号节点的治疗潜力，我将在模拟人类营养过剩引起的肥胖症的独立疾病小鼠模型中测试工作计划干预部分获得的知识。这是测量确切效应大小的关键，并为药物发现或临床研究奠定了基础，以评估针对肥胖和相关疾病的某些靶蛋白的治疗潜力。

The project‘s research program focuses on the application of the genetic model organism mouse, to study in vivo the mechanism of an acute reciprocal cross-regulation of adiponectin and leptin. Objective 1 "Determine whether or not and how adiponectin siganling through AdipoR1 and AdipoR2 regulates leptin production" and objective 2 "Determine whether or not and how leptin signaling through LepRb regulates adiponectin production", are subdivided in a discovery and intervention part. Discovery part: The diverse set of outstanding new mouse models will allow me to examine the spacio-temporal elucidation of AdipoR and LepR signaling. Combining an adipocyte specific doxycycline-inducible AdipoR double knockout mouse model and an adipocyte specific doxycycline-inducible LepR knockout mouse model will enable me to reflect both sides of the interaction. Intervention part: the most distinguished targets found to be regulated in adipocytes by the respective receptor signaling, will be manipulated by well established adeno-associated virus (AAV) gene transfer technology. The swift aquisition of mechanistical insights into the cross-regulation of adiponectin and leptin can be expected by my adipocyte selective AAV targeting approach. The alternative approach to use small molecule inhibitors will add to the diversity of methods. With objective 3 ,"Explore the therapeutic potential of manipulating pivotal signaling nodes of adiponectin/leptin cross-regulation in obesity, I will test knowledge gained under the work program’s intervention part in an independent disease mouse model mimicking human overnutrition-caused obesity. This is key to measure the exact effect size, and lays the foundation for drug discovery or clinical research to estimate the therapeutic potential of addressing certain target proteins in regards to obesity and associated diseases.