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Project 1: Brain steroid receptor coactivators and energy homeostasis

项目1：脑类固醇受体共激活剂和能量稳态

基本信息

批准号：
10421282
负责人：
YONG XU
金额：
$ 31.7万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421282
关键词：
Ablation Adipose tissue Age of Onset Animal Model Anorexia Attenuated Biochemical Body Weight Body mass index Brain Brain region CRISPR/Cas technology Characteristics Child Chronic Clustered Regularly Interspaced Short Palindromic Repeats Code Complex Cues Cultured Cells DNA Sequence Alteration Development Diet Dissociation Eating Energy Intake Energy Metabolism Ensure Equilibrium Estrogen Receptor alpha FOXO1A gene Fasting Fatty acid glycerol esters Feeding behaviors Genes Genetic Transcription Glucose High Fat Diet Homeostasis Hour Human Hyperphagia Hypothalamic structure Impairment Individual Insulin Knock-in Mouse Leptin Liver Locomotion Mediating Mediator of activation protein Metabolic Metabolism Modeling Molecular Mus Mutant Strains Mice Mutation Neurons Nuclear Receptors Nutritional Obesity PPAR gamma Pathway interactions Peripheral Phase Property Proteins Regimen Reservations Role Signal Transduction Signaling Molecule Stat3 protein Steroid Receptors System Technology Testing Thyroid Hormone Receptor Time Tissues Universities Weight Gain cohort diet-induced obesity energy balance exhibitions feeding insulin sensitivity metabolic phenotype mind control mouse model mutant new therapeutic target novel novel therapeutics nuclear receptor coactivator 1 obesity prevention obesity treatment overexpression prevent programs response severe early onset obesity transcription factor transcriptome

项目摘要

Project 1 - Project Summary Numerous nuclear receptors (NRs) or transcription factors (TFs) have been identified as important regulators of body weight. However, anti-obesity regimens targeting these individual molecules alone are far from satisfying. Coactivators interact with a broad range of NRs/TFs and may serve as master regulators that coordinate and synergize actions of multiple metabolic signals. High levels of Steroid Receptor Coactivator-1 and -2 (SRC-1 and SRC-2) are expressed in the hypothalamus, the key brain region controlling feeding and body weight balance. The pilot observations led to a hypothesis that hypothalamic SRC-1 and SRC-2 coactivate STAT3 and FoxO1, repectively, to provide coordinated control of energy metabolism. Aim 1 will determine whether hypothalamic SRC-1 fine-tunes STAT3 transcription activity to mediate the anti-obesity effects of leptin. Mouse models lacking or overexpressing SRC-1 only in leptin-responsive neurons have been generated. Metabolic parameters in response to different diets or to leptin treatment will be assessed in these mice. Importantly, the molecular mechanisms by which the SRC1-pSTAT3 complex regulates leptin signaling will be delineated. Aim 2 will determine whether human SRC-1 mutations impair leptin-STAT3 pathway in the hypothalamus and cause obesity. Using the CRISPR technology, a knockin mouse line has been generated to mimic a SRC-1 genetic mutation associated with human obesity. Metabolic phenotypes of these mice will be characterized, and leptin- STAT3 actions and STAT3 transcription activity will be evaluated. Aim 3 will determine whether hypothalamic SRC-2 coativates FoxO1 transcriptional activity to facilitate energy reservations. Mice lacking or overexpressing SRC-2 in mature POMC neurons have been generated, with/without FoxO1 overexpression. Metabolic phenotypes will be characterized in all these models and FoxO1 transcriptional activity will also be evaluated.

项目1--项目项目摘要： -- 许多核受体(NRs)或转录因子(TF)已被确定为全球最重要的监管机构。体重。然而，仅针对这些个体健康分子的抗肥胖治疗方案远远不能令人满意。共同激活者与范围广泛的一系列NRS/TF进行互动，他们可能还会作为主要的监管机构，负责协调他们和他们的关系。协同多种代谢信号的作用。高水平的类固醇激素受体和辅活化子-1和辅活化子-2(SRC--1)和。这些基因在下丘脑表达，下丘脑是控制进食和体重平衡的关键脑区。飞行员的观察结果导致他们提出了一个新的假设，即下丘脑SRC-1和SRC-2共同激活STAT3和FoxO1，。对此，我们的目标是为能量和新陈代谢提供一个协调的控制系统。这一目标将不会决定是否有下丘脑功能障碍。 SRC-1微调STAT3基因转录活性，以进一步调节瘦素的抗肥胖效应。小鼠模型缺乏。或者，SRC-1的过度表达只在瘦素反应的神经元中存在，这些神经元还没有生成。对不同饮食或瘦素治疗方案的反应将不会在这些小鼠身上进行评估。更重要的是，他们的分子水平。将不会详细描述由SRC1--pSTAT3组成的复合体调节瘦素信号传导的机制。确定人类SRC-1基因突变是否会损害下丘脑中瘦素-STAT3途径的表达，并导致这种情况。肥胖。由于使用了最新的CRISPR基因技术，已经成功地产生了一种新的敲击小鼠品系的基因，以模仿一种新的SRC-1基因。突变与人类肥胖有关。这些突变小鼠的代谢和表型将不会被描述为新的特征，包括瘦素-1。 STAT3的行动和STAT3的转录活性将不会被评估。STAT3的目标将不会决定是否会影响下丘脑。 SRC--2使FoxO1的转录调节活性降低，以进一步促进能量储备。小鼠缺乏表达或过度表达。在成熟的POMC中，SRC-2的神经元尚未生成，但有/没有FoxO1基因的过度表达。表型也将在所有这些模型中得到表征，FoxO1的转录活性也将得到进一步评估。