TARGETED ABLATION OF BRAIN ANGIOTENSINGERGIC SYSTEMS

描述：（改编自申请人的摘要）：大脑在大脑中起着关键的作用。 在维持心血管稳态中的作用。它接收，处理， 并整合反映血压和身体的神经体液信号， 有机体的流体状态。然后，它使适当的自主内分泌 和行为效应器系统来优化和恢复平衡。无序 心血管稳态的调节与疾病有关， 高血压尽管有多方面的证据表明， 血管紧张素系统在这两个复杂的过程中起着重要作用， 健康和疾病，缺乏对这一问题的基本方面的了解， 系统无法确定其确切作用。的不确定性 脑RAS在细胞水平上的组织是中心问题。 有证据表明，血管紧张素II的唯一已知前体，血管紧张素原， (AGT)集中在大脑的星形胶质细胞和神经元上。最近，PI 利用一种具有容易检测的AGT水平的转基因小鼠模型来绘制 脑AGT原位表达。PI发现AGT定位于星形胶质细胞 但其在神经元中的表达高度局限于两个 神经轴、前脑SFO-下丘脑-下面轴和脑干 臂旁杏仁核回路已知两者在心血管疾病中都很重要 体内平衡本提案的目标是确定相对功能 神经元和星形胶质细胞AGT在心血管调节中意义 vivo. PI将利用Cre-loxP技术，这是一种高度选择性的基因消融技术， 分别在两种基因中的每一种中靶向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对 每个脑血管紧张素能系统对长期心血管 将检查清醒大鼠中的调节。PI还将确定 AGT缺失是否导致心血管功能的变化 与神经细胞/纤维中Ang II免疫反应性的丧失相关。 最后，PI建议确定每个大脑的作用， RAS依赖性高血压遗传模型中的血管紧张素能系统， 非高血压动物。PI认为这些研究将解决 中枢RAS中神经元AGT与星形胶质细胞AGT长期探索问题 功能，并因此提供有关的机制， 心血管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.