Neuroendocrine dysfunction and hypertension

项目概要： 高血压影响三分之二的60岁以上的老年人，并显著增加痴呆症的风险 并加剧阿尔茨海默病（AD）的发病机制。AD是一种慢性神经退行性疾病 老年痴呆症是老年人中最常见的痴呆症形式，表现为丧失 认知功能AD通过细胞外含有淀粉样蛋白-β（Aβ）的积累来证实。 斑块和由聚集的tau蛋白形成的细胞内神经元缠结。虽然广泛 尽管已经进行了研究，但AD的发病机制主要是不确定的，并且仍然存在有效的治疗方法。 不可用.高血压与脑淀粉样蛋白、神经胶质细胞和神经胶质细胞密度增加有关。 神经纤维缠结和血管病变缠结。但 高血压中AD风险增加的病理生理学机制尚不清楚。 下丘脑-垂体-肾上腺（HPA）轴的过度活跃在AD和高血压患者中很常见。 用透射电镜观察了大鼠室旁核（PVN）内促肾上腺皮质激素释放激素（CRH）合成神经元 下丘脑（CRHPVN神经元）对HPA轴活性有重要调节作用。CRHPVN神经元活性是 自发性高血压大鼠（SHR）。因此，SHR将用于确定 CRHPVN神经元在高血压认知缺陷中的作用父R 01项目的范围是确定 CRHPVN神经元在高血压中的作用本补充申请旨在确定 CRHPVN神经元在高血压认知缺陷中的作用因此，本补充申请的范围是 在其母基金的范围内。初步研究发现，自发性高血压大鼠在大脑皮层表现出认知缺陷， 巴恩斯迷宫任务和新颖客观再认测验。海马长时程增强（LTP） 在SHR中显著降低。海马CRH和CRHR 1的表达水平分别为 增加我们将使用最近开发的化学遗传学方法来选择性地操纵CRH 神经元的活动和测试我们的中心假设，CRHPVN神经元的过度活跃是至关重要的 通过追求以下具体目标来参与高血压的认知缺陷：目标1是 确定高血压患者的认知缺陷和LTP受损是否归因于 CRHPVN神经元目的2是确定增强的CRH-CRHR信号是否参与认知功能， 高血压中的LTP缺陷和受损。拟议中的研究将大大提高人们对 原发性高血压认知缺陷的细胞机制。成功完成 这项研究将产生新的机制，负责认知缺陷的高血压和 靶向CRHPVN神经元和CRHR 1治疗高血压认知缺陷的基本原理。后 在成功完成建议的研究后，我们会发展一个新的项目，研究阿尔茨海默病的病理学， 如神经变性、突触功能障碍、tau蛋白病，通过靶向CRH-CRHR信号和HPA轴。

Project summary: Hypertension affects two-thirds of elders older than 60 years and significantly increases the risk of dementia and exacerbates the pathogenesis of Alzheimer’s Disease (AD). AD is a chronic neurodegenerative disorder that represents the most common form of dementia among the elderly, manifesting the loss of cognitive function. AD is confirmed by the accumulation of the extracellular amyloid-β (Aβ) containing plaques and intracellular neurofibrillary tangles formed by the aggregated tau protein. Although extensive studies have been carried out, the pathogenesis of AD is mainly undefined, and effective treatments are still unavailable. Hypertension is associated with an increased density of cerebral amyloid, neurofibrillary tangles, and angiopathy tangles in postmortem brains from hypertension patients. However, the pathophysiological mechanisms underlying the increased risk of AD in hypertension remain unclear. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is common in AD and hypertension patients. The corticotropin-releasing hormone (CRH) synthesizing neurons in the paraventricular nucleus (PVN) of the hypothalamus (CRHPVN neurons) are importantly regulate HPA axis activity. CRHPVN neuron activity is increased in spontaneously hypertensive rats (SHRs). Thus, SHRs will be used to determine the role of CRHPVN neurons in cognitive deficits in hypertension. The scope of the parent R01 project is to determine the role of CRHPVN neurons in hypertension. This supplemental application is to determine the role of CRHPVN neurons in cognitive deficits in hypertension. Thus, the scope of this supplemental application is within the scope of its parent grant. The preliminary study found that SHRs display cognitive deficits in the Barnes maze task and novel objective recognition test. Hippocampal long-term potentiation (LTP) was significantly decreased in SHRs. The expression levels of CRH and CRHR1 in the hippocampus were increased. We will use a recently developed chemo-genetic approach to selectively manipulate CRH neurons activity and test our central hypothesis that hyperactivity of CRHPVN neurons is critically involved in cognitive deficits in hypertension by pursuing the following specific Aims: Aim 1 is to determine if cognitive deficits and impaired LTPs in hypertension are attributed to hyperactivity of CRHPVN neurons. Aim 2 is to determine if enhanced CRH-CRHR signals are involved in cognitive deficits and impaired LTPs in hypertension. The proposed studies will greatly improve the understanding of the cellular mechanisms involved in cognitive deficits in primary hypertension. Successful completion of the proposed studies will yield novel mechanisms responsible for cognitive deficits in hypertension and an essential rationale for targeting CRHPVN neurons and CRHR1 to treat cognitive deficits in hypertension. After successfully completing the proposed studies, we will develop a new project to study AD pathologies, such as neurodegeneration, synaptic dysfunction, tauopathy, by targeting the CRH-CRHR signal and HPA axis.