Hypothalamic astrocyte-neuron relationship links overnutrition to hypertension

摘要/摘要 肥胖相关高血压(OHT)是一种病因流行的疾病，约75%的患者患有肥胖症 然而，高血压是很难控制的，而且这种临床困难涉及到的具体情况尚不清楚。 OHT的发病机制。最近认识到OHT的下丘脑神经元基础显著 由于肥胖诱导的IKKβ/NF-κB依赖的下丘脑炎症，这项研究的长期目标是 研究目的是研究介导OHT的下丘脑神经类型和分子级联反应。在预赛中 研究使用小鼠下丘脑星形胶质细胞IKKβ/NF-κB激活或抑制的模型，支持 已有证据表明，下丘脑星形胶质细胞在 导致高血压。因此，这一建议的假设是，在长期高脂饮食喂养下， 下丘脑星形胶质细胞IKKβ/NF-κB被激活，通过(A)汇聚 脂肪因子和血脑屏障(BBB)破坏导致的下丘脑ER应激的影响，(B) 星形细胞因子诱导的弓状DA神经元功能障碍对POMC神经元的激活作用，以及(C) 脑室旁核内α-msh和谷氨酸过多是由于星形胶质细胞清除受损所致。建议的三个目标是： (1)研究星形细胞IKKβ/NF-κB在特发性高血压中作用的神经解剖学和血脑屏障破坏基础；(2)研究 肥胖症中MBH星形胶质细胞-神经元关系的改变及其在OHT中的作用；(3)研究改变PVN 肥胖中星形胶质细胞-神经元的关系及其在OHT中的作用。实验将使用以下工具进行 位点和细胞特异性IKKβ/NF-κB操纵以及下游操纵的小鼠模型 星形胶质细胞和相关神经元的分子通路。将在这些人中检查血压表型 在饮食肥胖或拟议机制的遗传操作的背景下的模型。星形细胞改变， 下游程序，以及进一步的下游神经元变化将被严格分析。总的来说， 该项目的成功完成可以对OHT的下丘脑机制和 启发下丘脑星形胶质细胞靶向抗击本病的策略。

ABSTRACT/SUMMARY Obesity-related hypertension (OHT), an etiologically prevalent disorder accounting for ~75% of patients with hypertension, is however hard to control, and this clinical difficulty is related to the specific yet much unclear mechanism of OHT. Having recently appreciated that the hypothalamic neuronal basis of OHT is significantly due to obesity-induced IKKβ/NF-κB-dependent hypothalamic inflammation, the long-term objective of this research is to study hypothalamic neural types and molecular cascades that mediate OHT. In preliminary studies, using mouse models with hypothalamic astrocytic IKKβ/NF-κB activation or inhibition, supportive evidence has been obtained suggesting that hypothalamic astrocytes have site-specific multiple programs in causing hypertension. Hence, the hypothesis of this proposal is, under chronic high-fat diet feeding, hypothalamic astrocytic IKKβ/NF-κB is activated to cause OHT, mechanistically mediated by (a) converging effects of adipokines and consequent hypothalamic ER stress due to blood-brain barrier (BBB) breakdown, (b) activation of POMC neurons due to astrocytic cytokine-induced dysfunction of arcuate DA neurons, and (c) excess of α-MSH and glutamate in the PVN due to impaired astrocytic clearance. Three Aims are proposed to: (1) study the neuroanatomic and BBB breakdown basis for the role of astrocytic IKKβ/NF-κB in OHT; (2) study altered MBH astrocyte-neuron relationship in obesity and the contribution to OHT; and (3) study altered PVN astrocyte-neuron relationship in obesity and the contribution to OHT. Experiments will be carried out using mouse models of site- and cell-specific IKKβ/NF-κB manipulations as well as manipulations of the downstream molecular pathways in astrocytes and relevant neurons. Blood pressure phenotypes will be examined in these models in the context of dietary obesity or genetic manipulations of proposed mechanisms. Astrocytic changes, downstream programs, and further downstream neuronal alterations will be rigorously analyzed. Overall, successful completion of this project can yield new insights into the hypothalamic mechanism of OHT and enlighten the strategy of targeting hypothalamic astrocytic programs in combating this disease.