Neural Mechanisms of Obesity-Induced Hypertension

项目摘要 肥胖是高血压的主要原因，造成巨大的经济负担。然而，底层 机制基本上没有得到解决。这项提案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肥胖相关神经源性高血压中的因果作用。这 这个提议是基于我们最近对细胞内信号通路和神经元群体的鉴定 瘦素的高血压作用所必需的。我们假设瘦素在这个神经元集合上的信号传导 过度激活升压回路并导致肥胖引起的高血压。为了验证我们的假设，我将继续研究 的目标。目的1将确定瘦素信号通路如何在细胞类型特异性神经元群体 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如何 该信号通路有助于与心血管相关的电特性和突触输出。 调控目标2将研究肥胖如何在功能上重塑下游心血管回路。我会 联合收割机将体内生理学和化学遗传学技术与离体电生理学结合以鉴定细胞类型 对肥胖的特殊适应导致高血压。这项研究将为新的研究提供新的见解。 肥胖引起的高血压的分子和电路机制。此外，这些实验可能会导致 确定新的治疗肥胖引起的高血压的治疗靶点。

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.