Hypothalamic MANF and food-intake activity

下丘脑 MANF 和食物摄入活动

• 批准号: 9533710
• 负责人: Bing Yao
• 金额: $ 19.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9533710
• 关键词: Adult; Affect; Affinity; Affinity Chromatography; Astrocytes; Biology; Body Weight; Body Weight Changes; Brain; Brain region; CRISPR/Cas technology; Cardiovascular Diseases; Child; Chromatography; Complex; Databases; Dependovirus; Disease; Eating; Economics; Energy Intake; Energy Metabolism; Evaluation; Exhibits; Feeding behaviors; Food Energy; Genetic; Health; Healthcare; Homeostasis; Human; Hyperphagia; Hypertension; Hypothalamic structure; Incubated; Individual; Institutes; Ischemic Stroke; Knowledge; Lead; Link; Longitudinal Studies; Measures; Mediating; Molecular; Mus; Neuraxis; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Parkinson Disease; Phenotype; Play; Population; Protein Family; Proteins; Recombinants; Regulation; Reporting; Retinal Degeneration; Risk Factors; Role; Shapes; Signal Transduction; Societies; Spinocerebellar Ataxias; Stroke; Structure; System; Testing; Therapeutic; Transgenic Mice; Ubiquitin; Virus; Wild Type Mouse; base; bone; cancer type; cardiovascular risk factor; care burden; feeding; gel electrophoresis; genetic approach; insight; instrument; knock-down; metabolic phenotype; mouse model; neuron development; neurotrophic factor; novel; obesity development; overexpression; pandemic disease; polyglutamine; promoter; protective efficacy; tandem mass spectrometry

PROJECT SUMMARY Obesity is a major health problem worldwide and also a leading risk factor for various diseases, including type 2 diabetes, stroke, and cardiovascular diseases. Since neuronal activities in the brain are critical for maintaining systemic energy homeostasis, abnormal neuronal functions could lead to the development of obesity; thus, unraveling the complex neuronal mechanisms behind the central control of energy homeostasis is a high priority if we are to understand the biology of obesity and eventually treat or alleviate the health burdens it imposes. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified neurotrophic factor whose protective efficacy has been confirmed in several neurodegenerative diseases, but its endogenous function in the brain remains largely unknown. Recently, we generated a transgenic mouse model in which MANF is overexpressed in the central nervous system. Surprisingly, MANF transgenic mice become obese and exhibit hyperphagia. Moreover, we found endogenous MANF is highly enriched in the hypothalamus, and its expression is closely linked to the feeding status of the mice. These observations led us to hypothesize that MANF is involved in the hypothalamic control of food intake and energy homeostasis. Specific Aims for testing this hypothesis are: Aim (1) To evaluate the phenotypes of mice by increasing or reducing MANF expression in the hypothalamus. We will use virus transduction and CRISPR/Cas9 technology to modulate MANF levels specifically in the hypothalamus and evaluate the metabolic phenotypes of the mice after such modulations; Aim (2) To identify hypothalamic MANF partners in the regulation of energy homeostasis. We will perform affinity purification chromatography followed by tandem mass spectrometry to comprehensively study the MANF interactome in the hypothalamus and how such interactions shape the function of MANF. The results of this study will broaden our knowledge about the neuronal functions that regulate energy homeostasis. Understanding the molecular mechanisms of MANF signaling will yield valuable insights for developing potential MANF-based therapeutic strategies to treat obesity and related neurodegenerative disorders. !

项目概要 肥胖是世界范围内的一个主要健康问题，也是多种疾病的主要危险因素 疾病，包括 2 型糖尿病、中风和心血管疾病。由于神经元 大脑活动对于维持全身能量稳态至关重要 神经元功能可能导致肥胖的发生；从而解开复杂的 如果我们能够优先考虑能量稳态中央控制背后的神经机制 是了解肥胖的生物学原理并最终治疗或减轻其健康负担 强加。中脑星形胶质细胞源性神经营养因子（MANF）是一种新发现的 神经营养因子，其保护功效已在多种神经退行性疾病中得到证实 疾病，但其在大脑中的内源性功能仍然很大程度上未知。最近，我们 生成了一个转基因小鼠模型，其中 MANF 在中枢神经中过度表达 系统。令人惊讶的是，MANF 转基因小鼠变得肥胖并表现出食欲亢进。而且， 我们发现内源性MANF在下丘脑中高度富集，其表达量为 与小鼠的摄食状况密切相关。这些观察使我们推测 MANF 参与下丘脑对食物摄入和能量稳态的控制。 检验该假设的具体目的是： 目的 (1) 通过以下方式评估小鼠的表型： 增加或减少下丘脑中的 MANF 表达。我们将使用病毒转导 CRISPR/Cas9 技术专门调节下丘脑中的 MANF 水平 评估此类调节后小鼠的代谢表型；目标 (2) 识别 下丘脑 MANF 参与能量稳态的调节。我们将进行亲和力 纯化色谱法和串联质谱法进行全面研究 下丘脑中的 MANF 相互作用组以及这种相互作用如何影响下丘脑的功能 曼夫。这项研究的结果将拓宽我们对神经元功能的认识 调节能量稳态。了解 MANF 信号传导的分子机制将有助于 为开发基于 MANF 的潜在治疗策略提供宝贵的见解 肥胖和相关的神经退行性疾病。 ！