Role of Inflammatory Processes in Reward Network Alterations in Obesity

 描述(由申请人提供)：本提案的主要主题是识别与享乐进食行为(HEB)相关的大脑签名，以及炎症介质在塑造这些大脑签名中的作用。我还将评估使用有针对性的干预(认知行为疗法[CBT])的可行性，以抵消肥胖受试者这一亚组中扩展奖励网络中的假设变化。这一研究领域意义重大，因为食物摄入量中享乐成分的增加不再受体内平衡需求的驱动，可能在一些肥胖者中发挥重要的病理生理作用，但大脑偏向这种摄食行为改变的机制尚不完全清楚。在这里，我将使用炎症性基因表达谱来表明，不良经历通过神经炎症过程改变了扩展奖赏网络中的大脑特征。该提案首先描述了与heb相关的大脑信号。然后，通过外周血单个核细胞和血浆细胞因子测量的基因表达谱被识别，并与脑信号和Heb相关。CBT将被用于研究与加强扩展奖赏网络内前额叶区域的抑制影响有关的治疗效果，以及减少交感神经系统对免疫系统调节的增加，从而提供一种具有成本效益的对抗HEB的方法。先进和复杂的多变量分析技术将被用来整合来自多个神经成像来源的数据、基因图谱和行为数据，以便在确定与HEB相关的特征时确定不利环境因素的独特差异。这可能是一种与Heb相关的肥胖中枢生物标志物的敏感指标。考虑到性别和种族差异的模型将提高模型的有效性，并将有助于识别与Heb相关的肥胖风险增加的弱势群体。我有心理学背景，并寻求这个奖项的以下培训目标：(1)肥胖的病理生理学知识；(2)基因组分析技术，包括生物信息学技术；(3)代谢组学数据分析方面的知识和专长；(4)扩散张量磁共振分析方面的专门知识；(5)使用拓扑网络和系统生物分析技术(如聚类和分类分析)的高级数据驱动多变量技术；以及(6)将行为疗法应用于肥胖症的专业知识。应激神经生物学中心的工作环境为肥胖的神经遗传学研究培训提供了极好的基础设施。我将参加课程、研讨会和会议，以便全面了解肥胖的潜在生物学后遗症。与导师(Mayer[初选]、Pisegna、Li、Cole、Labus、Naliboff[共同导师])定期举行个人和小组会议。我打算申请一份 第三年拨款R03，第五年拨款R01。从长远来看，我计划在与肥胖健康差距相关的大脑-肠道相互作用方面建立一个独立的研究生涯。

 DESCRIPTION (provided by applicant): The main theme of this proposal is the identification of brain signatures associated with hedonic eating behaviors (HEB) and the role of inflammatory mediators in shaping these brain signatures. I will also evaluate the feasibility of using a targeted intervention (Cognitive Behavioral Therapy [CBT]) to counteract the hypothesized alterations within the extended reward network in this subgroup of obese subjects. This area of study is significant because increases in the hedonic component of food intake, which are no longer driven by homeostatic needs, are likely to play an important pathophysiological role in some obese individuals, but the mechanisms that bias the brain towards this alteration in ingestive behavior are incompletely understood. Here I will use inflammatory gene expression profiles to show that adverse experiences alter brain signatures within the extended reward network through the process of neuroinflammation. The proposal begins by characterizing brain signatures related to HEB. Then gene expression profiles as measured by peripheral blood mononuclear cells and plasma cytokines are identified and correlated with brain signatures and HEB. CBT will be used to investigate the therapeutic effect linked to strengthening inhibitory influences of prefrontal regions within the extended reward network, and reducing increased sympathetic nervous system modulation of the immune system, thereby offering a cost effective way of counteracting HEB. Advanced and sophisticated multivariate analytic techniques will be used to integrate the data from multiple neuroimaging sources, gene profiles, and behavioral data in order to determine the unique variance of adverse environmental factors in determining signatures associated with HEB. This may serve as a sensitive measure of central biomarkers in obesity related to HEB. A model that accounts for sex and race differences will increase the validity of the model, and will help identify disadvantaged groups who are at increased risk for obesity associated with HEB. I have a background in psychology and seek the following training goals from this award: (1) knowledge in the pathophysiology of obesity; (2) genomic analysis techniques including bioinformatics techniques; (3) knowledge and expertise in metabolomics data analysis; (4) specific expertise in diffusion tensor MRI analysis; (5) advanced data driven multivariate techniques using topological network and system biological analytical techniques (e.g. cluster and classification analysis); and (6) expertise in applying behavioral therapy to obesity. The work environment at the Center for Neurobiology of Stress provides an excellent infrastructure for training in neuro-genetic investigations of obesity. I will attend courses, workshops, and meetings in order to obtain a comprehensive understanding of the underlying biological sequelae of obesity. Regular individual and group meetings with mentors (Mayer [primary], Pisegna, Li, Cole, Labus, Naliboff [co-mentors]) have been set up. I plan to apply for a R03 grant by Year 3 and a R01 grant by Year 5. Long term, I plan to establish an independent research career in brain-gut interactions associated with health disparities in obesity.