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Regulation of Stable Fat Loss in a Model System

模型系统中稳定减脂的调节

基本信息

批准号：
7737151
负责人：
GENE E ROBINSON
金额：
$ 50.85万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7737151
关键词：
Adipocytes Adipose tissue Adult Alpha Cell Animal Model Animals Antibodies Arts Bees Biological Models Body Weight Body Weight decreased Brain Candidate Disease Gene Cells Coupling Data Employee Strikes Endocrine Energy Metabolism Environmental Risk Factor Fatty acid glycerol esters Gene Expression Gene Targeting Genes Genetic Models Genome Genomics Glandular Cell Glucagon Goals Honey Hormone Receptor Hormones Individual Insecta Insulin Invertebrates Juvenile Hormones Knock-out Life Link Lipids Mammals Measures Mediating Medicine Methodology Modeling Molecular Molecular Profiling Mus Obesity Overweight Peptides Pharmacotherapy Phase Play Population RNA Interference RXR Rattus Regulation Regulator Genes Research Research Personnel Role Shapes Signal Transduction Small Interfering RNA Statistical Models Structure Structure of beta Cell of islet Switch Genes System Systems Biology Techniques Testing Thyroid Hormones Tissues Transgenic Organisms Translating United States Weight Work abdominal fat adipokinetic hormone age related base brain cell energy balance fighting functional genomics genetic manipulation genome-wide insight insulin signaling markov model network models novel prevent public health relevance research study transcription factor transcriptomics

项目摘要

DESCRIPTION (provided by applicant): An important challenge in developing treatments that induce weight loss and prevent weight regain is to identify regulatory mechanisms that can be targeted for drug therapy. Invertebrate models have commonly been used to discover new candidate genes for medicine. This proposal will use the honey bee for this purpose because the bee undergoes a striking, predictable and stable loss of abdominal fat as it grows up. Naturally occurring, stable weight loss occurs in few species, and not at all in major genetic model systems. The bee is well suited to this task because it not only undergoes stable weight loss but also is amenable to considerable manipulation. The goal of this project is to use a new animal model, state-of-the-art genomics and systems biology techniques, and a novel insect-mammal coupling to identify genes that are important in regulating weight loss. We will first test the hypothesis that age-related changes in gene regulatory networks (GRNs) in brain circuits and fat cells are associated with stable lipid loss. We will develop detailed profiles of gene expression for abdominal fat cells and for three populations of brain cells that are important for the regulation of lipid stores. We will utilize a probabilistic Hidden Markov Modeling approach to develop a quantitative model of gene regulatory networks (GRNs) in these cells in order to identify key regulatory genes whose expression is causally linked to lipid loss. We will then test the hypothesis that age-related changes in gene regulatory networks associated with stable lipid loss are endocrine-mediated. We will test this hypothesis with a systems approach that combines genome-wide ChIP-chip analysis, RNAi, microarray expression profiling, and modeling. Preliminary results from both microarray and ChiP-chip experiments support both hypotheses. Finally, these studies will be used to identify "switch" genes that will be tested by genetic manipulations in mouse or rat to determine whether these genes regulate adiposity in mammals. The principal significance of this research is that it will provide important new insights into the molecular basis of the regulation of adiposity. PUBLIC HEALTH RELEVANCE: A major goal in fighting the obesity crisis in the United States is to develop treatments that induce weight loss and prevent weight regain, but in order to achieve this goal it is necessary to have a deep understanding of the mechanisms that control body weight. Honey bees, unlike most other animals, are able to achieve stable loss of fat tissue as part of their normal adult maturation. The goal of this proposal is to use genomic and systems biology techniques to identify "switch" genes that enable stable weight loss in the bee, and to test that these genes regulate body weight and energy metabolism in mammals.

描述(由申请人提供)：在开发诱导减肥和防止体重回升的治疗方法时，一个重要的挑战是确定可以作为药物治疗靶点的调节机制。无脊椎动物模型通常被用来发现新的医学候选基因。这项提议将使用蜜蜂来实现这一目的，因为蜜蜂在成长过程中会经历惊人的、可预测的和稳定的腹部脂肪损失。自然发生的、稳定的体重减轻发生在少数物种中，而在主要的遗传模型系统中根本不会发生。蜜蜂非常适合这项任务，因为它不仅可以稳定地减轻体重，而且还可以接受相当大的操控。这个项目的目标是使用一种新的动物模型，最先进的基因组学和系统生物学技术，以及一种新的昆虫-哺乳动物耦合来识别在调节减肥方面重要的基因。我们将首先测试这一假设，即大脑回路和脂肪细胞中与年龄相关的基因调控网络(GRN)的变化与稳定的脂肪损失有关。我们将开发腹部脂肪细胞和三类脑细胞的详细基因表达谱，这三类细胞对调节脂肪储存非常重要。我们将利用概率隐马尔可夫模型方法建立这些细胞中基因调控网络(GRN)的定量模型，以确定其表达与血脂损失相关的关键调控基因。然后，我们将检验这一假设，即与稳定的脂肪丢失相关的基因调控网络中与年龄相关的变化是由内分泌介导的。我们将用一种结合全基因组芯片分析、RNAi、微阵列表达谱分析和建模的系统方法来检验这一假设。微阵列和芯片实验的初步结果都支持这两种假设。最后，这些研究将被用来识别将通过在小鼠或大鼠身上进行遗传操作来测试的“开关”基因，以确定这些基因是否调节哺乳动物的肥胖。这项研究的主要意义在于，它将为肥胖调控的分子基础提供重要的新见解。与公共健康相关：美国抗击肥胖危机的一个主要目标是开发能够诱导体重减轻和防止体重回升的治疗方法，但为了实现这一目标，有必要对控制体重的机制有深入的了解。与大多数其他动物不同，蜜蜂能够在正常的成年成熟过程中稳定地失去脂肪组织。这项提议的目标是利用基因组和系统生物学技术来识别能够使蜜蜂稳定体重减轻的“开关”基因，并测试这些基因是否调节哺乳动物的体重和能量代谢。