Hypothalamic astrocyte-neuron relationship links overnutrition to hypertension

摘要/总结 肥胖相关性高血压（OHT）是一种病因学上流行的疾病，约占肥胖患者的75%， 然而，高血压很难控制，这种临床困难与具体的但尚不清楚的 OHT机制最近认识到，OHT的下丘脑神经元基础是显著的， 由于肥胖诱导的IKKβ/NF-κ B依赖性下丘脑炎症， 研究的目的是研究下丘脑神经类型和介导OHT的分子级联。初步 使用下丘脑星形胶质细胞IKKβ/NF-κB激活或抑制的小鼠模型的研究，支持 已经获得的证据表明，下丘脑星形胶质细胞具有位点特异性的多个程序， 引起高血压。因此，该建议的假设是，在慢性高脂肪饮食喂养下， 下丘脑星形胶质细胞IKKβ/NF-κB被激活引起OHT，其机制是通过（a）会聚 由于血脑屏障（BB B）破坏引起的脂肪因子和随后的下丘脑ER应激的作用，（B） 由于星形胶质细胞多巴胺诱导的弓状DA神经元功能障碍而激活POMC神经元，和（c） 由于星形胶质细胞清除受损，PVN中α-MSH和谷氨酸过量。提出了三个目标： (1)探讨星形胶质细胞IKKβ/NF-κB在OHT中作用的神经解剖学基础和BB B破坏基础;（2）研究 肥胖者MBH星形胶质细胞-神经元关系的改变及其对OHT的影响;（3）研究PVN的改变 肥胖中星形胶质细胞-神经元关系及其对OHT的影响。实验将使用 位点和细胞特异性IKKβ/NF-κB操纵以及下游IKKβ/NF-κB调控的小鼠模型 星形胶质细胞和相关神经元中的分子通路。血压表型将在这些 在饮食性肥胖或遗传操纵的背景下提出的机制的模型。星形胶质细胞改变， 下游程序和进一步的下游神经元改变将被严格分析。总的来说， 该项目的成功完成可以对OHT的下丘脑机制产生新的见解， 启发针对下丘脑星形胶质细胞程序在对抗这种疾病的策略。

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.