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/总结 肥胖相关性高血压 (OHT) 是一种病因学上普遍存在的疾病，约占肥胖症患者的 75% 高血压是一种很难控制的疾病，这种临床困难与具体的病因有关，但目前尚不清楚。 OHT 的机制。最近认识到 OHT 的下丘脑神经元基础是显着的 由于肥胖引起的 IKKβ/NF-κB 依赖性下丘脑炎症，这一目标的长期目标 研究目的是研究介导 OHT 的下丘脑神经类型和分子级联。在初步 研究使用下丘脑星形细胞 IKKβ/NF-κB 激活或抑制的小鼠模型，支持 已获得的证据表明下丘脑星形胶质细胞在 引起高血压。因此，该提案的假设是，在长期高脂肪饮食喂养下， 下丘脑星形胶质细胞 IKKβ/NF-κB 被激活导致 OHT，其机制是通过 (a) 汇聚介导的 脂肪因子的影响以及血脑屏障 (BBB) 破坏导致的下丘脑 ER 应激，(b) 由于星形细胞因子诱导的弓状 DA 神经元功能障碍而激活 POMC 神经元，以及 (c) 由于星形胶质细胞清除受损，PVN 中存在过量的 α-MSH 和谷氨酸。提出三个目标： (1) 研究星形细胞IKKβ/NF-κB在OHT中作用的神经解剖学和血脑屏障破坏基础； (二)学习 肥胖中 MBH 星形胶质细胞与神经元关系的改变及其对 OHT 的影响； (3) 研究改变的 PVN 肥胖中星形胶质细胞-神经元的关系及其对 OHT 的影响。实验将使用 位点和细胞特异性 IKKβ/NF-κB 操作以及下游操作的小鼠模型 星形胶质细胞和相关神经元中的分子途径。将在这些中检查血压表型 饮食肥胖背景下的模型或所提出机制的基因操作。星形胶质细胞的变化， 下游程序以及进一步的下游神经元改变将被严格分析。全面的， 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细胞计划对抗这种疾病的策略。