DHA Reverses Gene Network Signatures of Fructose-induced Metabolic Syndrome

 描述（由申请人提供）：与之前的预期相反，高果糖（HF）消耗正在成为代谢综合征（MetS）全球流行的关键因素，由于缺乏对HF作用介导机制的了解，引起了紧迫的关注。考虑到果糖在外周器官以及大脑能量稳态控制中的广泛作用，能够揭示HF对分子事件及其相互作用网络的影响的营养基因组学方法对于捕获MetS病因学的整个维度至关重要。我们假设HF诱导表观遗传变异，以改变MetS病理基础组织中基因网络的组织结构，从而重新编程代谢并增加MetS的风险。基因网络组织的信息可以用来指导干预逆转HF诱导的重编程，从而重新获得对代谢稳态的控制。我们提出了一个综合的营养基因组学研究，利用高通量基因组技术和网络建模方法的力量，再加上在小鼠体内实验研究和人类遗传研究，揭示HF对MetS病因基因组特征的影响。这项申请代表了一个独特的机会，以协同两个互补的多学科团队的专业知识-一个专门从事基因组学和其他专门从事营养研究-与优点联合收割机结合营养基因组学的方法和综合生理学，以促进我们的营养素对MetS的病因学的影响的理解。在目标1中，我们将使用下一代测序技术来确定HF消耗促进小鼠模型中所选MetS相关组织中DNA甲基化组以及转录组的大规模变化的能力，并鉴定MetS病理的分子特征。在目标2中，我们将评估高果糖如何影响网络中基因的组织，并确定可能导致网络动态变化的关键调控基因。将通过i）在转基因动物模型中靶向新型调控基因，和ii）在人类全基因组关联研究（GWAS）中评估新型调控因子/网络与代谢疾病的遗传关联，检测所鉴定的新型调控因子和基因网络与MetS的因果关联。最后，在目标3中，我们将通过证实DHA omega-3脂肪酸使表观遗传变异性和被HF破坏的基因网络正常化的能力来解决基因网络的治疗效用。我们的初步数据确实支持果糖诱导表观基因组和网络水平的扰动，这是逆转使用DHA。完成这项研究将提供急需的综合和系统水平的理解HF诱导的代谢综合征病理基础的基本分子过程。所获得的机制见解将有助于指导新的治疗靶点的选择和基于网络的营养策略的发展，以减轻MetS日益增长的健康负担。

 DESCRIPTION (provided by applicant): Contrary to previously expected, high fructose (HF) consumption is emerging as a key contributor to the worldwide epidemic of metabolic syndrome (MetS), posing pressing concerns for the lack of understanding of the mechanisms mediating the effects of HF. Considering the broad actions of fructose in peripheral organs as well as in the brain control of energy homeostasis, nutrigenomic approaches capable of revealing the impact of HF on webs of molecular events and their interactions are essential to capture the whole dimensionality of MetS etiology. We hypothesize that HF induces epigenetic variability to alter the organization of gene networks in tissues underlying the MetS pathology, thereby reprograming metabolism and increasing risks for MetS. The information on gene network organization can be utilized to guide interventions to reverse HF-induced reprogramming, leading to regain of control of metabolic homeostasis. We propose an integrative nutrigenomics study that harnesses the power of high throughput genomic technologies and network modeling approaches, coupled with in vivo experimental studies in mice and genetic studies in humans, to reveal the impact of HF on genomic signatures of MetS etiology. This application represents a unique opportunity to synergize the expertise of two complementary multidisciplinary teams - one specialized in genomics and the other specialized in nutritional research - with the merit to combine nutrigenomic approaches and integrative physiology to advance our understanding of the impact of nutrients on the etiology of MetS. In Aim 1, we will use next-generation sequencing technologies to determine the capacity of HF consumption to promote large- scale changes in the DNA methylome as well as in the transcriptome in selected MetS-related tissues in a mouse model, and identify molecular signatures of MetS pathology. In Aim 2, we will assess how high fructose affects the organization of genes in networks, and will identify key regulatory genes that may be responsible for the shifts in the network dynamic. The novel regulators and gene networks identified will be tested for causal association with MetS by i) targeting novel regulatory genes in genetically modified animal models, and ii) assessing novel regulators/networks for genetic association with metabolic diseases in human genome-wide association studies (GWAS). Lastly, in Aim 3, we will address the therapeutic utility of the gene networks by corroborating the capacity of DHA omega-3 fatty acid to normalize epigenetic variability and gene networks disrupted by HF. Our preliminary data indeed support that fructose induces epigenomic and network-level perturbations, which are reversed using DHA. Completion of the study will provide the much needed integrative and systems-level understanding of the basic molecular processes underlying HF-induced MetS pathology. The mechanistic insights obtained will help guide the selection of novel therapeutic targets and the development of network-based nutritional strategies for alleviating the growing health burden of MetS.