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.

我的职业目标是拥有一个独立的研究实验室，探索直接的神经元信号 室旁核（PVN）中影响高血压的通路。PVN是一个一体化的地区 下丘脑参与调节代谢过程，应激反应，心血管 功能/血压调节和自主神经系统总的假设是， 钠依赖性高血压与兴奋性神经传递增加有关， 高血压是PVN内变化的结果。部分原因是旁分泌信号的改变， 特别是一氧化氮（NO）和超氧化物（O2-）的相互作用，影响神经递质。此外， 细胞内信号传导家族、磷脂酰肌醇3-激酶（PI 3-激酶）和促分裂原的上调 活化蛋白激酶（MARK）进一步放大兴奋性神经传递，导致高血压。 其目标是使用一种综合的方法，利用生物化学，基因转移和生理学研究， 检查旁分泌和细胞内信号如何在PVN中改变以增加兴奋性 交感肾上腺功能和升高血压。为了实现这一目标，将讨论4个假设 （2在辅导期间和2在赠款的独立部分）：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- 肾包膜高血压的水平。假设2：在肾包膜高血压中，O2-升高， 与NO结合，减少生物可利用的NO并最终增加交感肾上腺功能和血液 压力假设#3：Ang II通过AT 1受体和谷氨酸通过NMDA受体利用共同的 信号通路涉及上调的PI 3-激酶信号级联，增加O2-，反过来， 高血压中的兴奋性神经传递假设#4：增强的O2水平作为信号 这些分子导致PVN中MAPK信号级联的激活，最终提高 高血压中的兴奋性神经传递确定旁分泌和细胞内信号传导的变化 信号通路对于理解信号通路对 神经递质活性和高血压。此外，由于PVN的综合性质，这些数据 也将提供一个信号在其他生理条件下的作用一瞥，如肥胖。