Neural Mechanisms of Obesity-Induced Hypertension

项目摘要摘要 肥胖是高血压的主要原因，给人们带来了巨大的经济负担。然而，潜在的 机制在很大程度上还没有解决。这项提议的目标是确定分子和神经通路。 导致肥胖引起的高血压。来自我们实验室和其他实验室的压倒性证据支持 脂肪细胞衍生激素瘦素在与肥胖相关的神经源性高血压中的因果作用。这 这一建议是基于我们最近确定的细胞内信号通路和神经元数量 瘦素的高血压作用所必需的。我们假设这个神经元上的瘦素信号是 过度激活加压回路，推动肥胖引起的高血压。为了检验我们的假设，我将继续 遵循目标。目标1将确定细胞类型特定神经元群体中的瘦素信号通路如何 促进肥胖症的功能障碍。我将使用体内和体外功能电路映射技术来定义 这一信号通路与心血管相关的电特性和突触输出有关 监管。目标2将研究肥胖如何从功能上重塑下游心血管回路。这就做 将体内生理和化学发生技术与体外电生理学相结合来鉴定细胞类型 对肥胖的特殊适应会导致高血压。这项拟议的研究将提供对小说的见解 肥胖性高血压的分子和电路机制。此外，这些实验可能会导致 肥胖性高血压治疗新靶点的确定。

Project Summary Abstract Obesity is a major cause of hypertension that imposes tremendous economic burdens. However, the underlying mechanisms are largely unresolved. The goal of this proposal is to identify molecular and neuronal pathways that contribute to obesity-induced hypertension. Overwhelming evidence from our lab and others support a causal role for the adipocyte-derived hormone, leptin, in neurogenic hypertension associated with obesity. This proposal is based on our recent identification of an intracellular signaling pathway and neuron population required for leptin’s hypertensive actions. We hypothesize that leptin signaling on this neuron ensemble hyperactivates pressor circuits and drives obesity-induced hypertension. To test our hypothesis, I will pursue the following aims. Aim 1 will determine how a leptin signaling pathway in a cell-type specific neuron population promotes dysfunction in obesity. I will use in vivo and ex vivo functional circuit mapping techniques to define how this signaling pathway contributes to electrical properties and synaptic output relevant to cardiovascular regulation. Aim 2 will investigate how obesity functionally reshapes downstream cardiovascular circuits. I will combine in vivo physiological and chemogenetic techniques with ex vivo electrophysiology to identify cell-type specific adaptations to obesity that contribute to hypertension. The proposed study will provide insights into novel molecular and circuit mechanisms in obesity-induced hypertension. Moreover, these experiments may lead to the identification of novel therapeutic targets for the treatment of obesity-induced hypertension.