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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 - 项目摘要许多核受体（NR）或转录因子（TF）已被确定为重要的调节因子体重。然而，仅针对这些单个分子的抗肥胖方案还远远不能令人满意。共激活因子与广泛的 NR/TF 相互作用，并且可以作为协调和调节的主要调节因子。协同多个代谢信号的作用。高水平的类固醇受体辅激活剂-1 和-2（SRC-1 和 SRC-2）在下丘脑中表达，下丘脑是控制进食和体重平衡的关键大脑区域。试点观察得出一个假设，即下丘脑 SRC-1 和 SRC-2 共同激活 STAT3 和 FoxO1，分别提供能量代谢的协调控制。目标 1 将确定下丘脑是否 SRC-1 微调 STAT3 转录活性以介导瘦素的抗肥胖作用。缺少鼠标型号或者仅在瘦素反应神经元中过度表达 SRC-1。代谢参数将评估这些小鼠对不同饮食或瘦素治疗的反应。重要的是，分子将描述 SRC1-pSTAT3 复合物调节瘦素信号传导的机制。目标 2 将确定人类 SRC-1 突变是否损害下丘脑的瘦素-STAT3 通路并导致肥胖。使用 CRISPR 技术，已生成模拟 SRC-1 基因的敲入小鼠品系与人类肥胖相关的突变。这些小鼠的代谢表型将被表征，瘦素- 将评估 STAT3 动作和 STAT3 转录活性。目标 3 将确定下丘脑是否 SRC-2 共激活 FoxO1 转录活性以促进能量储备。小鼠缺乏或过度表达成熟 POMC 神经元中的 SRC-2 已生成，有/没有 FoxO1 过表达。代谢所有这些模型都将表征表型，并且 FoxO1 转录活性也将被评估。