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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 -项目概要许多核受体（NR）或转录因子（TF）已被鉴定为细胞增殖的重要调节因子。然而，单独靶向这些单个分子的抗肥胖症方案远不能令人满意。共激活因子与广泛的NR/TF相互作用，并且可以充当协调和调节细胞内的细胞因子的主调节因子。高水平的类固醇受体辅激活因子-SRC-CRP 1和-SRC-CRP 2（SRC-CRP 1和SRC-CRP 2）可促进多种代谢信号的协同作用。 SRC-E2）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。初步观察导致了下丘脑SRC-B11和SRC-B12共激活STAT 3和FoxO 1的假设，分别提供协调控制的能量代谢。目标1将确定是否下丘脑 SRC-STAT 1精细调节STAT 3转录活性以介导瘦素的抗肥胖作用。或仅在瘦素-β 1反应性神经元中过表达SRC-B1。将在这些小鼠中评估对不同饮食或对瘦素治疗的反应。 SRC 1-pSTAT 3复合物调节瘦素信号传导的机制将被阐明。确定人类SRC-STAT 1突变是否损害下丘脑中的瘦素-STAT 3通路，使用CRISPR技术，已经产生了敲入小鼠系，以模拟SRC-CRIS 1基因。这些小鼠的代谢表型将被表征，并且瘦素-β 2受体将被检测。目的3：研究STAT 3的作用和转录活性。 SRC-RX 2共激活FoxO 1转录活性以促进能量储备。在有/没有FoxO 1过表达的情况下，已经在成熟POMC神经元中产生了SRC-B12。表型将在所有这些模型中表征，并且FoxO 1转录活性也将被评估。