Forebrain Plasticity in Hypertension

高血压中的前脑可塑性项目是一个新的多学科研究项目，专注于控制关键前脑中心和心血管系统之间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发病机制和随后的终末器官损伤，特别是脑血管损伤中的作用。PPG的中心主题关注穹窿下器官（SFO）（室周器官之一）和下丘脑室旁核（PVN）（SFO的主要输出通路）在交感神经过度活动和激素释放中的作用，这些都是血压升高的基础。中心假设是，在缓慢发展的高血压中，SFO-PVN轴中存在适应性修饰（神经可塑性），其变为适应不良，并为驱动高血压和脑血管功能障碍的神经体液失调奠定基础。每个项目都使用通过全身输注低剂量血管紧张素II（AngII）产生的高血压的临床相关小鼠模型来解决中心假设的特定方面。项目1将研究SFO中AngII诱导高血压的下游信号传导机制，重点关注前列腺素类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，这使得神经体液功能障碍成为高血压发展的基础。项目3将重点关注PVN的结构和功能修饰，这些修饰是导致绝经期女性对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，这些机制确保向大脑提供足够的血流。这些项目由行政核心，分子生物学-小鼠核心，神经解剖学-lmaaina核心和Radiotelemetrv核心支持。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既定目标。这些项目由一个高度互动的知名研究人员小组领导，并利用彼此的优势，使一个项目的科学产出与其他项目拟议的研究产生协同作用。因此，预计该计划的集体科学成果将大于其各个组成部分的总和。 高血压影响了近三分之一的普通人群，是困扰男性和绝经后女性的疾病负担的主要原因。该提案提供了一个前所未有的看神经体液功能障碍，导致高血压和脑血管功能障碍的细胞和分子基础。这些结果可能为高血压及其对脑的破坏性影响（如中风和痴呆）的新治疗提供合理的依据。

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.