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：
10153760
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153760
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-项目摘要许多核接收器（NRS）或转录因子（TF）已被确定为重要的调节剂体重。但是，仅针对这些单个分子的抗肥胖方案远非满意。共激活因子与广泛的NRS/TFS相互作用，并且可以用作协调和协同多个代谢信号的动作。高水平的类固醇受体共激活剂1和2（SRC-1和-2 SRC-2）在下丘脑（控制进食和体重平衡的关键大脑区域）中表达。试点观察结果导致了下丘脑SRC-1和SRC-2共激活STAT3和FOXO1的假设，分别提供对能量代谢的协调控制。 AIM 1将确定下丘脑是否 SRC-1微型STAT3转录活性以介导瘦素的抗肥胖作用。鼠标模型缺乏或仅在瘦素反应性神经元中过度表达SRC-1。代谢参数中在这些小鼠中将评估对不同饮食或瘦素治疗的反应。重要的是，分子 SRC1-PSTAT3复合物调节瘦素信号传导的机制将被描述。 AIM 2意志确定人类SRC-1突变是否会损害下丘脑中的瘦素-STAT3途径并引起肥胖。使用CRISPR技术，已经生成了敲击鼠标线以模仿SRC-1遗传与人肥胖相关的突变。这些小鼠的代谢表型将被表征，瘦素 - STAT3动作和STAT3转录活动将进行评估。 AIM 3将确定下丘脑是否 SRC-2涂层FOXO1转录活性，以促进能量储备。缺乏或过表达的小鼠已经产生了成熟的POMC神经元中的SRC-2，并且没有FOXO1过表达。代谢在所有这些模型中都将表征表型，并且还将评估FOXO1转录活性。