Long-Term Neural Determinants of Cardiovascular Diseases

神经源性心血管疾病（CVD）治疗新策略的开发 需要详细了解交感神经活动（SNA）的长期控制器。这一领域的进展需要在基因组、细胞、神经网络和整个动物水平上进行研究。单靠一个实验室或机构来完成这项任务，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，以促进我们对CVD神经源性基础的理解，最初的重点是血管紧张素II（AngII）-高血压盐模型（HTN）。有三个具体目标。在目的1中，我们将鉴定在AngII-盐模型中介导SNA变化的脑位点，在那些表达与HTN一致变化的位点中建立基因，并辨别对这些位点的兴奋性和抑制性输入的改变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。在目的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的、差异性的区域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AngII-盐HTN中的具体贡献。在目标3中，我们将确定与膳食盐和AngII相关的感觉输入的中断如何影响目标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视角和答案，最终导致开发新的基于遗传的神经源性HTN疗法，而这些疗法是使用更传统的岛状方法无法实现的。

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.