Paraventricular Nucleus Signaling Mechanisms in Hypertension

我的职业目标是拥有一个独立的研究实验室，探索直接神经元信号 影响高血压的室旁核(PVN)通路。PVN是一个一体化的区域 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。总体假设是 钠依赖型高血压与兴奋性神经传递增加和 由于室旁核内的变化而产生的高血压。部分原因是旁分泌信号的改变， 尤其是一氧化氮(NO)和超氧化物(O2-)的相互作用，影响神经递质。此外，一个 细胞内信号家族、磷脂酰肌醇3-激酶和有丝分裂原的上调 活化蛋白激酶(MARK)，进一步放大兴奋性神经传递，导致高血压。 目标是使用一种综合的方法，使用生化、基因转移和生理学研究，以 检查PVN中旁分泌和细胞内信号如何改变以增加兴奋性 交感神经-肾上腺功能和升高血压。为了实现这一目标，将提出4个假设 (2个在指导期间，2个在赠款的独立部分)：假设1：NAD(P)H 下丘脑室旁核中存在氧化酶，Ang II和谷氨酸使其活性增强，从而提高O2- 肾包膜高血压的水平。假设2：肾包膜高血压患者体内氧含量升高 与NO结合，减少生物可利用的NO，最终增加交感肾上腺功能和血液 压力。假设3：血管紧张素Ⅱ通过AT1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PI3-激酶信号级联，增加O2-，进而升高 高血压的兴奋性神经传递。假设4：O2-水平升高起信号作用 导致MAPK信号通路激活的分子在PVN中级联，最终升高 高血压的兴奋性神经传递。确定旁分泌和细胞内信号的变化 通路对于理解信号通路对 神经递质活性与高血压。此外，由于PVN的综合性，这些数据 这也将让我们得以一窥信号在其他生理状况中的作用，例如肥胖。

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.