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.

项目概要摘要肥胖是高血压的一个主要原因，它给人们带来了巨大的经济负担。该提案的目标是确定分子和神经通路。我们实验室和其他人的压倒性证据支持肥胖引起的高血压。脂肪细胞源性激素瘦素在与肥胖相关的神经源性高血压中的因果作用。该提案基于我们最近对细胞内信号通路和神经元群的识别瘦素的高血压作用是必需的，我们勇敢地面对这个神经元群上的瘦素信号。过度激活升压回路并导致肥胖引起的高血压。为了检验我们的假设，我将追求以下结论：以下目标将确定细胞类型特定神经元群中瘦素信号传导途径的情况。我将使用体内和离体功能回路映射技术来定义如何促进肥胖的功能障碍。该信号通路有助于与心血管相关的电特性和突触输出目标 2 将研究肥胖如何在功能上重塑下游心血管回路。将体内生理学和化学遗传学技术与离体电生理学相结合来识别细胞类型拟议的研究将为导致高血压的肥胖提供新的见解。此外，这些实验可能导致肥胖引起的高血压的分子和回路机制。确定治疗肥胖引起的高血压的新治疗靶点。