Synaptic mechanisms regulating sympathetic drive

调节交感神经驱动的突触机制

• 批准号: 8692568
• 负责人: Hui-Lin Pan
• 金额: $ 41.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692568
• 关键词: Animal Model; Biochemical Genetics; Brain; Brain Stem; Calcineurin; Calcineurin inhibitor; Complex; Data; Development; Essential Hypertension; Event; Feedback; Funding; Glutamates; Heart failure; Homeostasis; Hypertension; Hypothalamic structure; Inbred SHR Rats; Kidney Failure; Lead; Mediating; Metabotropic Glutamate Receptors; Molecular; Myocardial Infarction; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuraxis; Neurons; Pathogenesis; Patients; Phosphorylation; Play; Preparation; Proteins; Rattus; Research Design; Role; Secondary Hypertension; Secondary to; Site; Slice; Spinal Cord; Stroke; Synapses; Synaptic plasticity; Testing; Vasomotor; Voltage-Gated Potassium Channel; defined contribution; design; effective therapy; hypertension treatment; kidney vascular structure; novel; paraventricular nucleus; postsynaptic; presynaptic; transmission process

DESCRIPTION (provided by applicant): The sympathetic drive emanating from the brain is increased in animal models of hypertension and in patients with primary hypertension. The paraventricular nucleus (PVN) of the hypothalamus is an important site for the control of sympathetic outflow through its projections to sympathetically related sites in the brainstem and spinal cord. During the previous funding period, we showed that augmented glutamatergic input contributes to increased excitability of PVN presympathetic neurons and elevated sympathetic vasomotor tone in the animal model of hypertension. However, little is known about the molecular mechanisms underlying the sustained increase in glutamatergic input to the PVN in hypertension. Our recent study suggests that group I metabotropic glutamate receptors (mGluRs) in the PVN are critically involved in the support of elevated sympathetic outflow in hypertension. In this competing renewal proposal, we will use spontaneously hypertensive rats and renovascular hypertensive rats as animal models of hypertension to test our central hypothesis that group I mGluRs are upregulated at presynaptic and postsynaptic sites, which leads to increased glutamatergic input and excitability of PVN presympathetic neurons in hypertension. Our specific aims are to determine (1) the changes in the expression and distribution of group I mGluRs in the PVN during the development of hypertension; (2) the contribution of presynaptic group I mGluRs to augmented glutamatergic synaptic input to PVN presympathetic neurons in hypertension; (3)the downstream mechanisms mediating increased excitability of PVN presympathetic neurons by activation of postsynaptic group I mGluRs in hypertension; and (4) the changes in calcineurin activity and their contribution to increased group I mGluR and NMDA channel activity in the PVN in hypertension. The important roles of group I mGluRs and calcineurin in increased glutamatergic input in the PVN have not been recognized previously. Our proposed studies are expected to unravel a cascade of molecular events responsible for the sustained increase in sympathetic vasomotor tone in hypertension. This new information should have a major impact on our understanding of the fundamental neurogenic mechanisms underlying the development of primary and secondary hypertension and on the design of new treatments for hypertension.

描述（由申请人提供）：在高血压动物模型和原发性高血压患者中，来自大脑的交感神经驱动力增强。下丘脑的室旁核（PVN）是通过其投射到脑干和脊髓中交感相关部位来控制交感神经流出的重要部位。在之前的资助期间，我们表明，在高血压动物模型中，谷氨酸能输入的增加有助于增加PVN前交感神经元的兴奋性并提高交感血管舒缩张力。然而，对于高血压中 PVN 谷氨酸输入持续增加的分子机制知之甚少。我们最近的研究表明，PVN 中的 I 类代谢型谷氨酸受体 (mGluR) 在支持高血压中交感神经流出增加方面发挥着重要作用。在这项竞争性的更新提案中，我们将使用自发性高血压大鼠和肾血管性高血压大鼠作为高血压动物模型来测试我们的中心假设，即I组mGluR在突触前和突触后部位上调，从而导致高血压时PVN前交感神经元的谷氨酸输入和兴奋性增加。我们的具体目标是确定（1）高血压发展过程中PVN中I组mGluR的表达和分布的变化； (2)突触前 I 类 mGluR 对高血压患者 PVN 交感前神经元谷氨酸能突触输入的贡献； (3)高血压患者通过激活突触后I组mGluR介导PVN前交感神经元兴奋性增加的下游机制； (4) 高血压时钙调神经磷酸酶活性的变化及其对 PVN 中 I 组 mGluR 和 NMDA 通道活性增加的贡献。 I 组 mGluR 和钙调神经磷酸酶在增加 PVN 谷氨酸能输入中的重要作用以前尚未被认识到。我们提出的研究预计将揭示导致高血压交感血管舒缩张力持续增加的一系列分子事件。这些新信息应该对我们对原发性和继发性高血压发展的基本神经源性机制的理解以及高血压新疗法的设计产生重大影响。

项目成果

NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension.

• DOI: 10.1523/jneurosci.1346-12.2012
• 发表时间: 2012-06-20
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Ye ZY;Li DP;Byun HS;Li L;Pan HL
• 通讯作者: Pan HL

Protein kinase CK2 contributes to diminished small conductance Ca2+-activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension.

• DOI: 10.1111/jnc.12758
• 发表时间: 2014-09
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Pachuau J;Li DP;Chen SR;Lee HA;Pan HL
• 通讯作者: Pan HL

Regulation of Hypothalamic Presympathetic Neurons and Sympathetic Outflow by Group II Metabotropic Glutamate Receptors in Spontaneously Hypertensive Rats.

• DOI: 10.1161/hypertensionaha.113.01466
• 发表时间: 2013-08
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Ye ZY;Li DP;Pan HL
• 通讯作者: Pan HL

Protein kinase CK2 increases glutamatergic input in the hypothalamus and sympathetic vasomotor tone in hypertension.

• DOI: 10.1523/jneurosci.1147-11.2011
• 发表时间: 2011-06-01
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Ye ZY;Li DP;Li L;Pan HL
• 通讯作者: Pan HL