Paraventricular Nucleus Signaling Mechanisms in Hypertension

描述(由申请人提供)： 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。室旁核是下丘脑的一个综合区，参与新陈代谢过程、应激反应、心血管功能/血压调节和自主神经系统的调节。总体假设是钠依赖型高血压与兴奋性神经传递增加有关，而高血压是室旁核变化的结果。部分原因是旁分泌信号的改变，特别是一氧化氮(NO)和超氧阴离子(O2-)的相互作用，影响了神经递质。此外，细胞内信号家族磷脂酰肌醇的上调 3-激酶(PI3-激酶)和丝裂原活化蛋白激酶(MARK)，进一步放大兴奋性神经传递，导致高血压。我们的目标是使用一种综合的方法，利用生化、基因转移和生理学研究，研究PVN中的旁分泌和细胞内信号如何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：PVN中存在NAD(P)H氧化酶，其活性因Ang II和谷氨酸而增加，从而提高肾包膜高血压患者的O2-水平。假设2：肾包膜高血压患者体内O2-与NO结合，降低了生物可利用的NO，最终增加了交感肾上腺功能和血压。假设3：Ang II通过AT1受体，谷氨酸通过NMDA受体，利用共同的信号通路，包括上调的PI3-激酶信号级联，增加O2-，进而提高高血压的兴奋性神经传递。假设4：增强的O2-水平起信号分子的作用，导致PVN中MAPK信号级联激活，最终提高高血压患者的兴奋性神经传递。确定旁分泌和细胞内信号通路的变化对于了解信号通路对神经递质活性和高血压的影响具有重要意义。此外，由于PVN的综合性，这些数据还将提供信号在其他生理状况中的作用，如肥胖。(摘要结束)

DESCRIPTION (provided by applicant): 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 sympatho-adrenal 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. (End of Abstract)