Long-Term Neural Determinants of Cardiovascular Diseases

心血管疾病的长期神经决定因素

• 批准号: 7326827
• 负责人: John W Osborn
• 金额: $ 112.19万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-05 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326827
• 关键词: Address; Affect; Angiotensin II; Animal Model; Animals; Back; Beds; Biological Neural Networks; Blood; Blood Vessels; Blood Volume; Blood flow; Brain; Brain Stem; Brain region; Candidate Disease Gene; Cardiac; Cardiac Output; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular system; Cause of Death; Cells; Clinical; Collaborations; Condition; Conscious; Data; Denervation; Development; Diabetes Mellitus; Diet; Dietary Sodium; Disease; Disruption; Electric Capacitance; Elevation; Environment; Essential Hypertension; Functional disorder; Future; Gene Expression; Gene Expression Profile; Gene Transfer; Genes; Genetic; Genomics; Goals; Heart failure; Hindlimb; Human; Hypertension; Hypothalamic structure; In Situ Hybridization; Institution; Intake; Kidney; Knowledge; Laboratories; Laboratory Research; Lead; Link; Measurement; Mediating; Membrane; Metabolic Diseases; Methods; Microarray Analysis; Microinjections; Modeling; Molecular Profiling; Monitor; Nerve; Nervous system structure; Neural Pathways; Neurons; Numbers; Obesity; Organ; Pathogenesis; Pathway interactions; Pattern; Peptides; Peripheral; Peripheral Resistance; Personal Satisfaction; Physiological; Plasma; Play; Positioning Attribute; Pressoreceptors; Prevention strategy; Principal Investigator; Property; Rattus; Regulation; Research; Research Personnel; Resistance; Risk Factors; Role; Sensory; Signal Transduction; Site; Sodium; Sodium Chloride; Structure of area postrema; Sympathetic Nervous System; Synapses; System; Testing; Time; Transfection; Translating; Uncertainty; United States; Universities; Vascular resistance; Venous; Viral; Viral Genes; Work; Writing; base; body system; genetic profiling; hemodynamics; human disease; in vivo; network dysfunction; neural circuit; neurochemistry; neurogenic hypertension; neuroregulation; novel; novel strategies; novel therapeutics; osmoreceptor; paraventricular nucleus; pressure; programs; relating to nervous system; research study; response; sensor; vascular bed

Development of novel strategies for the treatment of neurogenic cardiovascular disease (CVD) requires a detailed understanding of the long-term controllers of sympathetic nerve activity (SNA). Advances in this field require research at the genomic, cellular, neural network and whole animal levels. The ability of a single laboratory, or institution, to carry out this task is difficult if not impossible. We propose the formation of an inter-institutional Consortium to advance our understanding of the neurogenic basis of CVD with the initial focus on the angiotensin II (Angll)-salt model of hypertension (HTN). There are 3 Specific Aims. In Aim 1 we will identify brain site(s) that mediate changes in SNA in the Angll-salt model, establish genes in those sites whose expressions change in concert with the HTN, and discern how alterations in excitatory and inhibitory inputs to these sites alter the gene expression profile, SNA, and mean arterial pressure (MAP). We will use viral gene transfer to normalize the gene expression profile, SNA, and MAP in Ang-salt HTN. In Aim 2 we will establish how Angll and dietary salt cause time-dependent, differential regional SNA and blood flow changes in conscious rats. These studies will establish the importance of capacitance and resistance changes, as well as specific contributions of the renal, splanchnic and hindlimb vascular beds in mediating Angll-salt HTN. In Aim 3 we will determine how disruption of sensory inputs linked to dietary salt and Angll affect the pathways characterized in Aim 1, and the SNA and cardiovascular response patterns characterized in Aim 2. We feel this integrative approach will provide fertile ground for the development of a greater understanding of the mechanisms that link the nervous system and CVD. We are confident that the inter-institutional collaboration of the Consortium will lead to new perspectives and answers that will ultimately lead to the development of novel genetic-based therapies for neurogenic HTN not achievable using more conventional insular approaches.

开发治疗神经源性心血管疾病（CVD）的新策略 需要详细了解交感神经活动（SNA）的长期控制器。该领域的进步需要在基因组、细胞、神经网络和整个动物水平上进行研究。单个实验室或机构执行这项任务的能力即使不是不可能，也是很困难的。我们建议成立一个机构间联盟，以增进我们对 CVD 神经源性基础的理解，最初重点关注高血压 (HTN) 的血管紧张素 II (AngII)-盐模型。有 3 个具体目标。在目标 1 中，我们将识别 Angll-salt 模型中介导 SNA 变化的大脑位点，在这些位点中建立其表达与 HTN 一致变化的基因，并辨别这些位点的兴奋性和抑制性输入的变化如何改变基因表达谱、SNA 和平均动脉压 (MAP)。我们将使用病毒基因转移来标准化 Ang-salt HTN 中的基因表达谱、SNA 和 MAP。在目标 2 中，我们将确定 AngII 和膳食盐如何在清醒大鼠中引起时间依赖性、差异性区域 SNA 和血流变化。这些研究将确定电容和电阻变化的重要性，以及肾、内脏和后肢血管床在介导 Angll-盐 HTN 中的具体贡献。在目标 3 中，我们将确定与膳食盐和 Angll 相关的感觉输入的破坏如何影响目标 1 中表征的途径，以及目标 2 中表征的 SNA 和心血管反应模式。我们认为这种综合方法将为更好地理解神经系统和 CVD 之间的联系机制提供肥沃的土壤。我们相信，该联盟的机构间合作将带来新的观点和答案，最终导致开发出使用更传统的岛状方法无法实现的神经源性高血压的新型基因疗法。