Integrative Neurobiology of Cardiovascular Regulation

描述(由申请者提供)：本项目资助项目继续关注心血管调节的综合神经生物学。现在已经是第40个年头了，它代表了爱荷华州心血管研究中心的一个主要科学重点。这一更新的力量是基于其高级领导层的凝聚力和协同作用，其概念和方法与新研究人员的不断演变，以及从发现机制到将其转化为动物模型和人类疾病状态的连续努力。这四个项目代表了中枢神经激素过程的功能整合，这些过程通过相互依赖的分子机制，包括神经可塑性、氧化和炎症，导致焦虑、高血压和血管损伤等病理状态。项目I：“中枢神经可塑性在高血压敏化中的位置和机制”(Johnson，Kwitek)探索了通过上调关键大脑核团中的信号分子来诱发高血压的机制，这些核团包括控制血压的神经网络中对血管紧张素/醛固酮敏感的成分。项目II：“焦虑是否通过炎症和交感神经激活导致血管功能障碍？”(Haynes，Fiedorowicz，Piells)认为，外周和中枢(大脑)的血管功能障碍是炎性氧化过程的病理基础，这种过程会增加患有严重焦虑的人类的交感神经活性和心血管风险。项目三：“在高血压的遗传模型中，先天免疫系统的神经激素调节是促炎的”(Abboud，Ballas，Zavazava)确定了胆碱能和ATI受体对高血压血管和肾脏损害的炎症免疫病理过程的强烈调节影响。项目IV：“蛋氨酸亚硫氧化物还原酶A：一种新的自主神经调节和高血压末端器官损伤的分子决定因素”(Chapleau，Anderson，Weiss)探索了针对特定大脑部位和血管肌肉的氧化过程变化，从而改变高血压和血管病理过程的能力。探索了高血压和血管病变中的炎症和氧化过程的新概念。技术方法和动物模型已经很好地建立起来了，高血压、焦虑、自主神经障碍和血管病理的分子机制在翻译上也存在着主题上的趋同。共同的线索创造了智力结构，在这种结构中，综合结果将远远大于各组成部分的总和。

DESCRIPTION (Provided by applicant): This Program Project Grant continues to focus on Integrative Neurobiology of Cardiovascular Regulation. Now in its 40th year, it represents a major scientific emphasis of the Cardiovascular Research Center at lowa. The strength of this renewal is based on the cohesion and synergy of its senior leadership, its constant evolution in concepts and approaches with new investigators and the continuum of the effort from discovery of mechanisms to their translation into disease states in animal models and humans. The four projects represent a functional integration of central neurohormonal processes which through interdependent molecular mechanisms involving neuroplasticity, oxidation, and inflammation induce pathological states of anxiety, hypertension and vascular damage. Project I: "Sites and Mechanisms of CNS Neuroplasticity in the Sensitization of Hypertension" (Johnson, Kwitek) explores mechanisms that induce hypertension through the upregulation of signaling molecules in the key brain nuclei comprising the Angiotensin/Aldosterone sensitive components of the neural network controlling blood pressure. Project II: "Does Anxiety Cause Vascular Dysfunction Through Inflammation and Sympathetic Activation?" (Haynes, Fiedorowicz, Pierce) considers vascular dysfunction peripherally as well as centrally (cerebrally) as pathological underpinnings of an inflammatory oxidative process that increases sympathetic activity and cardiovascular risks in humans with severe anxiety. Project III: "Neurohormonal Regulation of the Innate Immune System is Proinflammatory in a Genetic Model of Hypertension" (Abboud, Ballas, Zavazava) identifies a strong regulatory influence of cholinergic and ATI receptors on the inflammatory immune pathological process in hypertension with vascular and renal damage. Project IV: "Methionine Sulfoxide Reductase A: a novel Molecular Determinant of Autonomic Regulation and Hypertensive End-Organ Damage" (Chapleau, Anderson, Weiss) explores the ability to target changes in the oxidative process to specific brain sites and vascular muscle and thereby alter the course of hypertension and vascular pathology. Novel concepts about inflammatory and oxidative processes in hypertension and vasculopathy are explored. The technical approaches and animal models are well established, and there is a thematic translational convergence of molecular mechanisms in hypertension, anxiety, dysautonomia and vascular pathology. Common threads create the intellectual fabric where the integrated outcome will be far greater than the sum of the components.