Weight loss-induced modification of the genomic network underlying obese asthma

 描述（由申请人提供）：体重减轻诱导的肥胖型哮喘基础基因组网络修饰。该项目的主要科学目标是了解减肥改善哮喘症状的分子机制。肥胖和哮喘是世界上最常见的两种慢性疾病，并且都是发病的主要遗传原因。肥胖既是一个重要的哮喘易感性危险因素，也是哮喘控制和严重程度的主要调节因素。重要的是，它是可改变的风险因素：肥胖哮喘患者通过节食，运动和/或减肥手术进行重大体重减轻（5-50%），通常在呼吸道症状和哮喘控制方面有实质性改善。哮喘和肥胖之间的这些临床和流行病学关系已经得到了很好的建立，但它们的潜在分子机制还没有建立起来。阐明体重减轻引起的基因组修饰导致哮喘控制的改善将具有重大的科学和公共卫生意义。 我建议使用基因组流行病学和网络方法来识别肥胖与哮喘关系背后的可修饰基因和途径。鉴于血液和脂肪组织的基因表达谱先前已经鉴定了分别与哮喘和肥胖表型相关的生物学上合理的基因的聚类组（例如，炎症和免疫过程），我假设在人类转录组中（i）存在一个或多个对肥胖哮喘特异的局部基因共表达模块;（ii）哮喘患者的体重减轻导致哮喘控制的改善，同时诱导关键共表达模块成员表达的特异性改变。我将首先使用先前发表的数据来定义肥胖性哮喘的初步基因共表达模块，然后在一个专门开发的新队列中进行测试，以纵向评估哮喘-肥胖重叠的分子关系。这将是一个前瞻性队列，肥胖个体（n = 100，约50%患有哮喘）接受腹腔镜袖状胃切除术（LSG），手术前和术后3个月测量疾病相关基因表达和哮喘/肥胖表型数据。合作者共享的与减肥干预相关的较小的未发表基因组数据集将进一步复制与LSG队列中肥胖哮喘变化相关的基因网络。

 DESCRIPTION (provided by applicant): WEIGHT LOSS-INDUCED MODIFICATION OF THE GENOMIC NETWORK UNDERLYING OBESE ASTHMA. The primary scientific objective of this project is to understand the molecular mechanisms by which weight loss improves asthma symptoms. Obesity and asthma are two of the most common chronic medical conditions in the world and are each major heritable causes of morbidity. Obesity is both a significant asthma susceptibility risk factor and a major modifier of asthma control and severity. Importantly, it is modifiable risk factor: obese asthmatics who undergo major weight reductions (5-50%) through dieting, exercise, and/or bariatric surgery often have substantial improvements in respiratory symptoms and asthma control. These clinical and epidemiological relationships between asthma and obesity are well established; what are not are their underlying molecular mechanisms. Elucidating the genomic modifications induced by weight loss that lead to improvements in asthma control would be of great scientific and public health importance. I propose to use genomic epidemiological and network approaches to identify modifiable genes and pathways underlying the obesity-asthma relationship. Given that gene expression profiling of blood and adipose tissues has previously identified clustered sets of biologically plausible genes separately related to asthma and obesity phenotypes (e.g., inflammatory and immune processes), I hypothesize that within the human transcriptome (i) there exist one or more local gene co-expression modules specific to obese asthma; and (ii) that weight loss in asthmatics results in improvements in asthma control coincident with induction of specific alterations in the expression of critical co-expression module members. I will first use previously published data to define preliminary gene co-expression modules of obese asthma to then be tested in a novel cohort specifically developed to longitudinally assess the molecular relationships underlying the asthma-obesity overlap. It will be a prospective cohort of obese individuals (n = 100, ~50% with asthma) undergoing laparoscopic sleeve gastrectomy (LSG) with disease-relevant gene expression and asthma/obesity phenotype data measured both prior to the surgery and post-operatively at three months. Smaller unpublished genomic datasets related to weight loss interventions shared by collaborators will further replicate gene networks associated with changes in obese asthma in the LSG cohort.