TARGETED ABLATION OF BRAIN ANGIOTENSINGERGIC SYSTEMS

描述：(改编自申请者的摘要)：大脑扮演着关键的角色 在维持心血管内环境平衡中的作用。它接收、处理、 并整合反映血压和身体状况的神经体液信号 有机体的流体状态。然后，它参与适当的自主内分泌。 和行为效应器系统，以优化和恢复平衡。无序的 心血管内稳态的调节与疾病有关，如 高血压。尽管有多条证据表明脑肾素 血管紧张素系统在这些复杂的过程中起着重要的作用 健康和疾病，缺乏对这一基本方面的理解 系统阻止了确定其确切的角色。不确定的是 在细胞水平上大脑RAS的组织是中心问题。 有证据表明，血管紧张素原是血管紧张素Ⅱ的唯一已知前体 (AGT)定位于脑内的星形胶质细胞和神经元。最近《少年派》 利用了一种转基因小鼠模型，这种转基因小鼠的AGT水平很容易检测到 脑内AGT的原位表达。PI发现AGT定位于星形胶质细胞 但它在神经元中的表达高度限制在两个 神经轴、前脑SFO-下丘脑-面下轴和脑干 臂旁-杏仁核环路。众所周知，两者在心血管疾病中都很重要。 动态平衡。这项建议的目标是确定相对功能性 神经元和星形细胞AGT在大鼠心血管调节中的意义 活着。PI将使用Cre-loxP技术，这是一种高度选择性的基因消融 在两者中分别针对AGT转基因缺失的策略 神经回路和星形胶质细胞。永久性消融AGT的疗效观察 脑血管紧张素能系统对长期心血管的影响 将检查清醒大鼠的调节。PI还将决定 AGT缺失是否会导致心血管功能的改变 与神经细胞/纤维中Ang II免疫反应性的丧失有关。 最后，PI建议确定这些大脑中每一个的角色 RAS依赖型高血压遗传模型中的血管紧张素能系统 在非高血压动物身上。国际刑警组织相信，这些研究将解决 中枢RAS中神经元AGT与星形胶质AGT的长期研究问题 功能，并因此提供了有关 心血管内稳态的正常和病理调节。

DESCRIPTION: (Adapted from Applicant's abstract): The brain plays a critical role in the maintenance of cardiovascular homeostasis. It receives, processes, and integrates neurohumoral signals that reflect the blood pressure and body fluid status of the organism. It then engages appropriate autonomic endocrine and behavior effector systems to optimize and restore balance. Disordered regulation of cardiovascular homeostasis is associated with diseases such as hypertension. Although multiple lines of evidence suggest that the brain-renin angiotensin system figures prominently in these complex processes in both health and disease, a lack of understanding of fundamental aspects of this system has prevented from determining its precise role. Uncertainty about the organization of the brain RAS at the cellular level is the central issue. Evidence suggests that the only known precursor of Ang II, angiotensinogen (AGT) is localized to both astrocytes and neurons in the brain. Recently the PI has utilized a transgenic mouse model with easily detectable AGT levels to map brain AGT expression in situ. The PI found that AGT is localized to astrocytes in widespread regions but its expression in neurons is highly restricted to two neural axes, the forebrain SFO-hypothalamic-hypofacial axis and the brainstem parabrachial-amygdala circuit. Both are known to be important in cardiovascular homeostasis. The goal of this proposal is to determine the relative functional significance of neuronal and astrocytic AGT in cardiovascular regulation in vivo. The PI will utilize Cre-loxP technology, a highly selective gene ablation strategy to target deletion of AGT transgene separately in each of the two neural circuits and in astrocytes. The effect of permanent ablation of AGT in each of the brain angiotensinergic systems on long term cardiovascular regulation in conscious rat will be examined. The PI will also determine whether changes in cardiovascular function resulting from AGT deletion correlate with a loss of Ang II immunoreactivity in nerve cells/fibers. Finally, the PI proposes to determine the role of each of these brain angiotensinergic systems in a genetic model of RAS-dependent hypertension and in non-hypertensive animals. The PI believes that these studies will address the long-sought question of neuronal versus astroglial AGT in central RAS function and as such provide fundamental knowledge about the mechanisms of normal and pathological regulation of cardiovascular homeostasis.