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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）：在开发诱导体重减轻和防止体重反弹的治疗方法时，一个重要的挑战是确定可作为药物治疗靶点的调节机制。无脊椎动物模型通常用于发现新的医学候选基因。这个建议将使用蜜蜂用于此目的，因为蜜蜂在成长过程中经历了惊人的，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，而不是在所有主要的遗传模型系统。蜜蜂非常适合这项任务，因为它不仅经历稳定的体重减轻，而且还适合大量的操纵。该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-哺乳动物偶联来识别在调节体重减轻中重要的基因。我们将首先检验脑回路和脂肪细胞中基因调控网络（GRNs）中与年龄相关的变化与稳定的脂质损失相关的假设。我们将开发腹部脂肪细胞和三个群体的脑细胞的基因表达的详细资料，这些细胞对脂质储存的调节很重要。我们将利用概率隐马尔可夫建模方法来开发这些细胞中基因调控网络（GRNs）的定量模型，以确定其表达与脂质损失有因果关系的关键调控基因。然后，我们将测试的假设，与稳定的脂质损失相关的基因调控网络的年龄相关的变化是内分泌介导的。我们将测试这一假设与系统的方法，结合全基因组ChIP芯片分析，RNAi，微阵列表达谱，和建模。微阵列和芯片芯片实验的初步结果支持这两种假设。最后，这些研究将被用于确定“开关”基因，这些基因将通过在小鼠或大鼠中进行遗传操作来测试，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，它将为肥胖调节的分子基础提供重要的新见解。公共卫生关系：在美国，对抗肥胖危机的一个主要目标是开发诱导体重减轻和防止体重反弹的治疗方法，但为了实现这一目标，有必要深入了解控制体重的机制。与大多数其他动物不同，蜜蜂能够实现脂肪组织的稳定损失，作为其正常成年成熟的一部分。该提案的目标是使用基因组和系统生物学技术来识别使蜜蜂稳定减肥的“开关”基因，并测试这些基因调节哺乳动物的体重和能量代谢。