Lateral hypothalamic regulation of sympathetic nerve activity and blood pressure

下丘脑外侧调节交感神经活动和血压

• 批准号: 9249964
• 负责人: Huxing Cui
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249964
• 关键词: Adrenergic Fibers; Affect; Agonist; Animals; Beds; Blood Pressure; Blood Pressure Monitors; Body Weight; Brain; Cardiovascular Diseases; Cardiovascular Physiology; Chronic Disease; Congestive Heart Failure; Coupled; Cre-LoxP; Data; Development; Exhibits; Fiber; Genetic; Genetic Techniques; Goals; Homeostasis; Human; Hypertension; Hypothalamic structure; Kidney; Knock-out; Knockout Mice; Lateral; Lateral Hypothalamic Area; Lead; Leptin; Measurement; Mediating; Melanocortin 4 Receptor; Metabolic; Molecular; Morbid Obesity; Mus; Myocardial Infarction; Nerve; Neurons; Obesity; Pathway interactions; Peripheral; Pharmacology; Physiological; Play; Population Study; Prevalence; Process; Public Health; Receptor Signaling; Regulation; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Stroke; System; Techniques; Technology; Testing; Tissues; Work; awake; base; design; effective therapy; hypertension treatment; improved; in vivo; innovation; leptin receptor; mad itch virus; mouse model; neural circuit; neurogenic hypertension; normotensive; novel; novel therapeutics; obesity treatment; optogenetics; public health relevance; receptor expression; receptor-mediated signaling; relating to nervous system; selective expression

 DESCRIPTION (provided by applicant): Obesity and hypertension are serious public health concerns. Population studies indicate that at least two- thirds of the prevalence of hypertension can be directly attributed to obesity. Obesity-induced hypertension is associated with sympathetic overactivity and evidence indicates that signaling through both leptin receptor and melanocortin-4 receptor is critical for this process. However, the underlying neural basis of this association remains incompletely understood. Our long-term goal is to delineate the neural circuits that mediate obesity- induced sympathetic overactivity and hypertension. The rationale for this proposed research is that understanding the specific brain leptin and melanocortin circuits that mediate sympathetic outflow and blood pressure will help to develop more selective pharmacologic strategies that will allow effective treatment of hypertension and obesity. We have recently identified a unique subpopulation of neurons in the lateral hypothalamic area that co-express both leptin receptor and melanocortin-4 receptor. The central hypothesis is that, in the context of obesity and hyperleptinemia, both leptin receptor and melanocortin-4 receptor signaling in this subpopulation of lateral hypothalamic area neurons is augmented to cause sympathetic overactivity and hypertension. In order to directly test the components of this hypothesis, the following Specific Aims have been generated: 1) To determine if MC4R signaling in the LHA is necessary and sufficient to regulate renal SNA and mediates obesity-associated increases in blood pressure; and 2) To determine if LepR signaling in the LHA is necessary and sufficient to regulate renal SNA and mediates obesity-associated increases in blood pressure; and 3) To test if selective optogenetic modulation of activity of LHA LepR+ neurons regulates renal SNA and ameliorates obesity-associated increases in blood pressure. We will test if manipulating leptin and melanocortin signaling and neuronal activity in the LHA in the context of obesity affect sympathetic outflow and cardiovascular function. The proposed research is innovative because it will combine multiple state-of-the-art techniques, including Cre/loxP, optogenetics, direct multi-fiber recording of sympathetic nerve activity and radiotelemetry measurement of blood pressure, to test a novel brain circuit that contributes to obesity-induced sympathetic overdrive and hypertension in mice. The proposed research is significant because it will improve our understanding of the molecular and neural basis of obesity-induced hypertension and identifies novel therapeutic opportunities to effectively treat hypertension associated with the development of obesity. We believe that this work will contribute to a better understanding of how brain networks and signaling pathways lead to the development of neurogenic hypertension.

 描述（适用提供）：肥胖和高血压是严重的公共卫生问题。人口研究表明，至少三分之二的高血压患病率可以直接归因于肥胖症。肥胖引起的高血压与交感神经过度活动有关，证据表明，通过瘦素受体和黑色素质素-4受体的信号传导对于此过程至关重要。但是，该关联的基本神经基础仍然没有完全理解。我们的长期目标是描述介导观察引起的交感神经过度和高血压的中性回路。这项拟议的研究的基本原理是，了解介导交感神经出口和血压的特定脑瘦素和黑色皮质素回路将有助于制定更具选择性的药理策略，从而有效治疗高血压和肥胖。我们最近确定了在下丘脑侧面共表达瘦素受体和黑色素皮质素-4受体的神经元的独特亚群。中心假设是，在肥胖和高稀释血症的背景下，在下丘脑区域神经元的这种亚群中，瘦素受体和黑色皮质素-4受体信号传导可增加以引起交感神经过度活动和高血压。为了直接检验该假设的组成部分，已经产生了以下特定目的：1）确定LHA中的MC4R信号是否需要调节肾SNA并介导与肥胖相关的血压升高； 2）确定LHA中的LEPR信号是否足以调节肾脏SNA并介导与肥胖相关的血压升高； 3）测试LHA LEPR+神经元活性的选择性光遗传学调节是否调节肾脏SNA并改善与肥胖相关的血压增加。我们将测试在肥胖症的背景下，在LHA中操纵LHA的瘦素和黑色素性信号和神经元活性是否会影响交感神经出口和心血管功能。拟议的研究具有创新性，因为它将结合多种最新技术，包括CRE/LOXP，光遗传学，交感神经活动的直接多纤维记录和血压的放射性电子事测量，以测试一种新型的脑电路，从而有助于肥胖引起的交感神经过量和小鼠的交感神经过度和高血压。拟议的研究很重要，因为它将提高我们对肥胖诱导的高血压的分子和神经基础的理解，并确定新型的治疗机会，以有效治疗与肥胖发展相关的高血压。我们认为，这项工作将有助于更好地理解大脑网络和信号通路如何导致神经源性高血压的发展。