Neural Mechanisms of Obesity-Induced Hypertension

肥胖引起的高血压的神经机制

基本信息

批准号：
10677977
负责人：
Connor Laule
金额：
$ 3.44万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677977
关键词：
Adipocytes Adult Affect Blood Pressure Brain Brain Stem Cardiovascular Diseases Cardiovascular system Cells Complex Data Disease Economic Burden Electrophysiology (science)Energy Metabolism FRAP1 gene Fiber Functional disorder Genetic Techniques Goals Health Hormones Hypertension Hypothalamic structure Impairment Kidney Knockout Mice Learning Leptin Leptin resistance Maps Melanocortin 4 Receptor Metabolic Methods Molecular Nerve Neurons Obese Mice Obesity Output Pathway interactions Photometry Physiological Population Pro-Opiomelanocortin Property Public Health Publishing Regulation Research Role Shapes Signal Pathway Signal Transduction Stroke Structure of nucleus infundibularis hypothalami Synapses System Techniques Testing Thinness Transgenic Mice United States Viral Work blood pressure elevation blood pressure reduction blood pressure regulation cardiometabolism cardiovascular risk factor cell type conditional knockout diet-induced obesity electrical property experimental study hypertensive in vivo insight leptin receptor neural circuit neurogenic hypertension neuromechanism new therapeutic target novel obesity development obesity treatment patch clamp preservation

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.

项目摘要摘要肥胖是造成高血压的主要原因，不可能是巨大的经济伯恩斯。但是，基础机制在很大程度上尚未解决。该建议的目的是识别分子和神经元途径这有助于肥胖引起的高血压。我们实验室和其他人的压倒性证据支持与肥胖相关的神经源性高血压中脂肪细胞衍生的马酮的因果作用。这建议基于我们最近对细胞内信号通路和神经元种群的识别瘦素的高血压动作所必需的。我们假设该神经元集合上的瘦素信号传导过度激活压压电路并驱动肥胖引起的高血压。为了检验我们的假设，我将追求以下目标。 AIM 1将确定细胞类型特异性神经元种群中的瘦素信号通路如何促进肥胖症功能障碍。我将使用体内和Ex Vivo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规定。 AIM 2将研究肥胖在功能上如何重塑下游心血管回路。我会将体内生理和化学遗传学技术与离体电生理学结合在一起，以鉴定细胞类型对有助于高血压的肥胖症的特定适应。拟议的研究将提供有关新颖的见解肥胖诱导的高血压中的分子和电路机制。而且，这些实验可能导致鉴定用于治疗肥胖诱导高血压的新型治疗靶标。