Neural Mechanisms of Obesity-Induced Hypertension

项目摘要

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.