Hypothalamic NF-kB and astrocytic programs in obesity

肥胖症中的下丘脑 NF-kB 和星形细胞程序

基本信息

批准号：
10380845
负责人：
Dongsheng Cai
金额：
$ 52.34万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380845
关键词：
Acute Address Affect Antidiabetic Drugs Astrocytes Autophagocytosis Biology Brain Cells Cellular Metabolic Process Chronic Cytokine Receptors Data Development Diabetes Mellitus Disease Equilibrium FRAP1 gene GABA Receptor GABA transporter Gene Expression Genetic High Fat Diet Hypothalamic structure Impairment In Vitro Inflammatory Insulin Interleukin-9 Intervention Lead Leptin Link Metabolic Metabolic Diseases Modeling Molecular Molecular Genetics Mus NF-kappa B Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Pharmacology Phosphotransferases Physiological Prediabetes syndrome Process Production Publishing Receptor Signaling Regulation Research Resistance Role STAT3 gene Series Signal Transduction Structure of nucleus infundibularis hypothalami Therapeutic Effect Tyrosine 3-Monooxygenase cytokine design diet-induced obesity dopaminergic neuron energy balance experimental study extracellular feeding gamma-Aminobutyric Acid in vivo inhibitor insulin signaling knock-down metabolic abnormality assessment novel obesogenic programs response success therapy design uptake

项目摘要

ABSTRACT/SUMMARY Having appreciated the role of pro-inflammatory IKKβ/NF-κB pathway in the hypothalamic mechanism of obesity, the objective of this research is to study how hypothalamic neurons and astrocytes are programmatically involved. Through recent studies including preliminary experiments on mice with hypothalamic astrocytic IKKβ/NF-κB activation or inhibition, supportive evidence was obtained to suggest that astrocytes in the mediobasal hypothalamus (MBH) have multiple programs through IKKβ/NF-κB for being responsible for metabolic imbalance. Hence, the hypothesis of this proposal is, sustained activation of astrocytic IKKβ/NF-κB in the MBH under chronic high-fat diet feeding leads to altered astrocyte-neuron relationships in the MBH, at least due to an impairment in astrocyte-dependent GABA clearance and also an enhancement in astrocytic cytokine production – which employ GABA and cytokine receptor signaling to influence the responsible neurons, resulting in multiple forms of neuronal dysregulation on metabolic balance which underlie obesity and pre-diabetic development. Three Aims are designed to study (1) astrocytic IKKβ/NF-κB–autophagy axis in linking hypothalamic neurons to metabolic dysregulation, (2) IKKβ/NF-κB- dependent astrocytic clearance of GABA in linking POMC neuronal inhibition to obesity, and (3) IKKβ/NF-κB- driven astrocytic cytokines in linking other responsive hypothalamic neurons to disease development. A combination of cellular, molecular, genetic, physiological and pharmacological approaches will be used to analyze astrocytic biology and functions, the overall and local influences on neurons, and their mechanistic roles for obesity and pre-diabetes. Successful completion of this project will be important for understanding the hypothalamic basis of obesity and diabetes and provide new paradigms in designing interventional strategies.

摘要/总结了解促炎 IKKβ/NF-κB 通路在下丘脑机制中的作用肥胖，这项研究的目的是研究下丘脑神经元和星形胶质细胞如何通过最近的研究，包括对小鼠的初步实验。下丘脑星形细胞 IKKβ/NF-κB 激活或抑制，获得的支持性证据表明下丘脑内侧基底层 (MBH) 中的星形胶质细胞通过 IKKβ/NF-κB 具有多种程序因此，该提议的假设是，持续激活。长期高脂饮食喂养下MBH中的星形胶质细胞IKKβ/NF-κB导致星形胶质细胞神经元改变 MBH 中的关系，至少是由于星形胶质细胞依赖性 GABA 清除的损害以及增强星形细胞细胞因子的产生——利用 GABA 和细胞因子受体信号传导影响负责的神经元，导致多种形式的神经代谢平衡失调肥胖和糖尿病前期发育的三个目标旨在研究（1）星形胶质细胞。 IKKβ/NF-κB–自噬轴将下丘脑神经元与代谢失调联系起来，(2) IKKβ/NF-κB– GABA 的依赖性星形细胞清除与 POMC 神经元抑制与肥胖有关，以及 (3) IKKβ/NF-κB- 驱动星形细胞因子将其他反应性下丘脑神经元与疾病发展联系起来。细胞、分子、遗传、生理和药理学方法的结合将被用于分析星形胶质细胞的生物学和功能、对神经元的整体和局部影响及其机制成功完成该项目对于了解肥胖和糖尿病前期的作用非常重要。肥胖和糖尿病的下丘脑基础，并为设计干预策略提供新的范例。