Paraventricular Nucleus Signaling Mechanisms in Hypertension

高血压的室旁核信号传导机制

• 批准号: 7691736
• 负责人: CARRIE A NORTHCOTT
• 金额: $ 24.9万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691736
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Aminobutyric Acids; Angiotensin II; Autonomic nervous system; Baroreflex; Bioavailable; Biochemical; Blood Pressure; Cardiovascular Physiology; Cells; Data; Equilibrium; Family; Gene Transfer; Generations; Glutamate Receptor; Glutamates; Goals; Grant; Hypertension; Hypothalamic structure; Kidney; Laboratories; Laboratory Research; Lead; Left; MAP Kinase Gene; Maintenance; Mediating; Mediation; Mentors; Metabolic syndrome; Metabolism; Mitogen-Activated Protein Kinases; N-Methyl-D-Aspartate Receptors; Nature; Nerve; Neurons; Neurotransmitters; Nitric Oxide; Obesity; Oxidases; Paracrine Communication; Pathway interactions; Phase; Physiological; Population; Reactive Oxygen Species; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Sodium; Spinal Cord; Stimulus; Subfornical Organ; Superoxides; Testing; Third ventricle structure; Up-Regulation; biological adaptation to stress; blood pressure regulation; career; energy balance; gamma-Aminobutyric Acid; hindbrain; neurotransmission; paracrine; paraventricular nucleus

My career goal is to have an independent research laboratory exploring the direct neuronal signaling pathways in the paraventricular nucleus (PVN) that influence hypertension. The PVN is an integrative region of the hypothalamus involved in the regulation of metabolic processes, stress responses, cardiovascular function/blood pressure regulation and the autonomic nervous system. The overall hypothesis is that sodium-dependent hypertension is associated with increased excitatory neurotransmission and hypertension that is the result of changes within the PVN. In part due to altered paracrine signaling, specifically nitric oxide (NO) and superoxide (O2-) interactions, influencing neurotransmitters. In addition, an upregulation of intracellular signaling families, phosphatidylinositol 3-kinase (PI3-kinase) and mitogen activated protein kinase (MARK), further amplifies excitatory neurotransmission resulting in hypertension. The goal is to use an integrative approach, using biochemical, gene transfer and physiological studies, to examine how both paracrine and intracellular signaling changes in the PVN to increase excitatory sympathoadrenal function and elevate blood pressure. To achieve this goal 4 hypotheses will be addressed (2 during the mentored period and 2 during the independent portion of the grant): Hypothesis #1: NAD(P)H oxidase is present in the PVN and its activity is increased by Ang II and glutamate, thus elevating O2- levels in renal wrap hypertension. Hypothesis #2: In renal wrap hypertension, there is elevated O2- which combines with NO, reducing bioavailable NO and ultimately increasing sympathoadrenal function and blood pressure. Hypothesis #3: Ang II via the AT1 receptor and Glutamate via the NMDA receptor utilize common signaling pathways involving an upregulated PI3-kinase signaling cascade, increasing O2-, in turn, elevating excitatory neurotransmission in hypertension. Hypothesis #4: Enhanced O2- levels act as signaling molecules that lead to the activation of the MAPK signaling cascade in the PVN, ultimately elevating excitatory neurotransmission in hypertension. Identifying the changes in paracrine and intracellular signaling pathways is significantly important for understanding the impact signaling pathways have on neurotransmitter activity and hypertension. In addition, due to the integrative nature of the PVN, these data will also provide a glimpse at the role of signaling in other physiological conditions, such as obesity.

我的职业目标是让一个独立的研究实验室探索直接的神经元信号传导 影响高血压的室室核（PVN）中的途径。 PVN是一个综合区域 与代谢过程，压力反应，心血管调节有关的下丘脑 功能/血压调节和自主神经系统。总体假设是 依赖钠的高血压与增加的兴奋性神经传递和 高血压是PVN内变化的结果。部分由于旁分泌信号的改变， 特别是一氧化氮（NO）和超氧化物（O2-）相互作用，影响神经递质。另外，一个 细胞内信号传导家族的上调，磷脂酰肌醇3-激酶（PI3-激酶）和有丝分裂原 活化的蛋白激酶（MARK）进一步放大了兴奋性神经传递，导致高血压。 目的是使用生化，基因转移和生理研究使用综合方法来 检查旁分泌和细胞内信号如何变化PVN以增加兴奋性 交感神经功能并升高血压。为了实现这一目标，将解决4个假设 （在指导期间2，在赠款的独立部分中2个）：假设＃1：NAD（p）h 氧化酶存在于PVN中，其活性通过ANG II和谷氨酸盐增加，从而升高O2-- 肾包裹高血压的水平。假设2：在肾包裹高血压中，有升高的O2- 结合否，减少生物利用度否，并最终增加交感神经功能和血液 压力。假设3：ANG II通过AT1受体和谷氨酸通过NMDA受体利用常见 信号通路涉及上调的PI3-激酶信号级联反应，而O2-又增加了 高血压中的兴奋性神经传递。假设4：增强的O2-水平充当信号 导致PVN中MAPK信号级联激活的分子，最终升高 高血压中的兴奋性神经传递。识别旁分泌和细胞内信号的变化 途径对于理解影响信号传导途径对 神经递质活性和高血压。此外，由于PVN的综合性质，这些数据 还将瞥见信号在其他生理条件（例如肥胖症）中的作用。