Hypothalamic astrocyte-neuron relationship links overnutrition to hypertension

下丘脑星形胶质细胞-神经元关系将营养过剩与高血压联系起来

• 批准号: 10090630
• 负责人: Dongsheng Cai
• 金额: $ 61.13万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090630
• 关键词: Accounting; Address; Affect; Astrocytes; Autophagocytosis; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Brain; Brain region; Cells; Cellular Metabolic Process; Chronic; Cleaved cell; Clinical; Disease; Dopamine Agonists; Endocrinology; Enzymes; Etiology; Functional disorder; Glutamate Transporter; Glutamates; High Fat Diet; Hypertension; Hypothalamic structure; IL6ST gene; Impairment; Inflammation; Inflammatory; Intervention; Kidney; Leptin; Link; Mediating; Medicine; Modeling; Molecular; Nature; Neurons; Neurosecretory Systems; Obesity; Obesity Related Hypertension; Overnutrition; Pathway interactions; Patients; Phenotype; Physiology; Plant Roots; Process; Production; Publications; Receptor Signaling; Reporting; Research; Role; Site; TNF gene; Testing; Transforming Growth Factor beta; Tyrosine 3-Monooxygenase; Work; adipokines; alpha-Melanocyte stimulating hormone; cell type; cytokine; dietary; dopaminergic neuron; endoplasmic reticulum stress; experimental study; extracellular; feeding; genetic manipulation; improved; inhibition of autophagy; insight; interest; mouse model; novel; overexpression; paraventricular nucleus; programs; receptor; relating to nervous system; stem; success

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.

摘要/摘要 肥胖相关高血压（OHT），这是一种病因，占约75％的患者的病因 高血压，但是很难控制，并且该临床难度与特定但尚不清楚的 OHT机制。最近对OHT的下丘脑神经元基础显着 由于肥胖诱导的IKKβ/NF-κB依赖性下丘脑感染，这是此的长期目标 研究是研究介导OHT的下丘脑神经元类型和分子级联反应。在初步 研究，使用具有下丘脑星形胶质细胞IKKβ/NF-κB激活或抑制作用的小鼠模型，支持性 已经获得了证据，表明下丘脑星形胶质细胞具有特定地点的多个程序 引起高血压。因此，在慢性高脂饮食喂养下，该提议的假设是 下丘脑星形胶质细胞IKKβ/NF-κB被激活以引起OHT，由（a）收敛于机械介导 由于血脑屏障（BBB）破裂引起的脂肪因子和随之而来的下丘脑ER应激的影响，（b） 由于星形细胞因子诱导的弧形DA神经元功能障碍而引起的POMC神经元的激活，并且（C） 由于星形胶质细胞清除率受损，PVN中的α-MSH和谷氨酸过量过量。提出了三个目标： （1）研究星形胶质细胞IKKβ/NF-κB在OHT中的作用的神经解剖学和BBB分解基础； （2）研究 肥胖症中的MBH星形胶质细胞神经元关系改变了肥胖和对OHT的贡献； （3）研究改变了PVN 肥胖症中的星形胶质细胞关系和对OHT的贡献。实验将使用 位点和细胞特异性IKKβ/NF-κB操作的小鼠模型以及下游的操作 星形胶质细胞和相关神经元中的分子途径。在这些中将检查血压表型 在饮食肥胖或对拟议机制的遗传操作的背景下的模型。星形细胞变化， 下游程序和进一步的下游神经元改变将进行严格分析。全面的， 成功完成该项目可以对OHT和OHT下丘脑机制的新见解和 启发针对下丘脑星形胶质细胞方案来对抗这种疾病的策略。