FOREBRAIN PLASTICY IN HYPERTENSION

高血压的前脑可塑性计划是一个新的多学科研究计划，专注于控制关键前脑中枢和心血管系统之间的神经体液相互作用的基本生物学过程。该计划的长期目标是阐明这些中心在高血压的发病机制以及随后的终末器官损伤，特别是脑血管损伤中所起的作用。PPG的中心主题集中在穹隆下器(SFO)和下丘脑室旁核(PVN)在交感神经过度活动和激素释放中的作用。SFO是脑室周围器官之一，下丘脑室旁核是SFO的主要输出途径。中心假说是，在缓慢发展的高血压中，SFO-PVN轴存在适应性修饰(神经可塑性)，导致适应性不良，并为推动高血压和脑血管功能障碍的神经体液调节失调奠定基础。每个项目都使用一个临床上相关的高血压小鼠模型来解决中心假说的一个特定方面，该模型是通过全身注射低剂量血管紧张素II(Ang11)产生的。项目1将研究血管紧张素转换酶11诱导高血压的SFO下游信号机制，重点关注前列腺素作为重要中介的作用。项目2将研究PVN中关键的结构和功能适应不良机制，这些机制使神经体液功能障碍成为高血压发展的基础。项目3将侧重于PVN的结构和功能修改，这是更年期女性高血压易感性增加的原因。项目4将讨论SFO-PVN轴在高血压对重要脑血管调节机制的有害影响中的作用，这些调节机制确保向大脑提供足够的血流。这些项目得到了一个行政核心、一个分子生物学-鼠标核心、一个神经解剖学核心和一个无线电技术核心的支持。该计划的一个主要优势是每个项目都结合了分子、神经解剖学、神经生理学和心血管综合方法来实现所述目标。这些项目由一组高度互动的知名研究人员领导，并建立在彼此优势的基础上，使一个项目的科学成果与其他项目中提出的研究产生协同作用。因此，该计划的集体科学成果预计将大于其个别组成部分的总和。 高血压影响了近三分之一的总人口，是困扰男性和绝经后女性疾病负担的主要原因。该提案提供了一个前所未有的视角，揭示了导致高血压和脑血管功能障碍的神经体液功能障碍的细胞和分子基础。这一结果可能为治疗高血压及其对大脑的破坏性影响(如中风和痴呆症)的新疗法提供合理的依据。

The Forebrain Plasticity in Hypertension Program is a new multidisciplinary research program focused on the fundamental biological processes governing the neurohumoral interaction between key forebrain centers and the cardiovascular system. The long-term objective of the program is to elucidate the role of these centers in the pathogenesis of hypertension and in the ensuing end-organ damage, particularly cerebrovascular damage. The central theme of the PPG focuses on the role of the subfornical organ (SFO), one of the circumventricular organs, and the hypothalamic paraventricular nucleus (PVN), the main output pathway of the SFO, in the sympathetic overactivity and hormonal release underlying the increase in blood pressure. The central hypothesis is that in slow-developing hypertension there are adaptive modifications (neuroplasticity) in the SFO-PVN axis that turn maladaptive, and set the stage for the neurohumoral dysregulation driving the hypertension and the cerebrovascular dysfunction. Each project addresses a specific facet of the central hypothesis using a clinically relevant mouse model of hypertension produced by systemic infusion of a low dose of angiotensin II (Angll). Project 1 will examine the downstream signaling mechanisms in SFO by which Angll induces the hypertension, focusing on the role of prostanoids as essential intermediaries. Project 2 will examine critical structural and functional maladaptive mechanisms in the PVN, which enable the neurohumoral dysfunction underlying the development of hypertension. Project 3 will focus on the structural and functional modifications in the PVN that are responsible for the increased susceptibility to hypertension in menopausal females. Project 4 will address the role of the SFO-PVN axis in the deleterious effects of hypertension on vital cerebrovascular regulatory mechanisms that assure an adequate blood flow delivery to the brain. The Projects are supported by an Administrative Core, a Molecular Biology-Mouse Core, a Neuroanatomv-lmaaina Core and a Radiotelemetrv Core. A major strength of the program is that each project combines molecular, neuroanatomical, neurophysiological and cardiovascular integrative approaches to achieve the stated goals. The projects are led by a highly interactive group of established investigators and build on each other's strengths so that the scientific output of one project interacts synergistically with the research proposed in other projects. Thus, the collective scientific outcome of the Program is anticipated to be greater than the sum of its individual components. Hypertension affects nearly one third of the general population and is a major cause of the disease burden afflicting men and post-menopausal women. The proposal provides an unprecedented look at the cellular and molecular underpinnings of the neurohumoral dysfunction that leads to hypertension and cerebrovascular dysfunction. The results may provide the rational bases for new treatments for hypertension and its devastating effects on the brain, such as stroke and dementia.