Genomic Analyses for Elucidating Novel Targets for Symptoms Management

大多数症状是多因素的起源与遗传和环境因素有助于个体差异。基于生物学假设的候选基因研究已经被用来鉴定复杂性状（如疼痛）中的相关遗传变异。然而，复杂的影响因素和参与不同症状的数千种分子使得很难检测出个体对疾病独特易感性的遗传变异。单个基因中的常见变异不太可能对复杂性状起主导作用;相反，每个基因的贡献似乎是微妙的，作用于多个生物途径中的一个，使得其信号难以检测。 疾病知识的迅速增长和应用强大和高容量技术的能力的综合影响，提高了人们对用于各种症状管理的更有效和更安全的药物的期望。开发用于症状管理的新治疗策略也关键地依赖于识别新的靶分子和定义特定类型的病症的表型。因此，该项目的第一步是确定实验和临床表型的特征。 最近，我们启动了多个采用下一代测序（NGS）技术的项目，该技术使我们能够进行整个和/或靶向基因组测序。将继续研究遗传和表观遗传因素对各种疾病和/或病症症状的作用。 例如，在神经系统疾病，如急性疼痛，轻度创伤性脑损伤和创伤后应激障碍，我们正在使用基因分型，基因和蛋白质表达，以及患者报告的结果，以更好地了解这些因素之间的相互作用和众多的生物/机械途径，包括炎症级联反应。从战区回来的士兵的基因表达谱在多个会议（CNRM和ESTA会议）上提出，并已提交出版。两个表观遗传学研究使用DNA甲基化染色质免疫沉淀，然后全基因组规模测序进行了从平民和军事群体。运动相关脑震荡患者的表观遗传变化将在ASHG会议上介绍。第二次军人创伤后应激障碍患者表观遗传学研究已完成样本测序，数据正在分析中。使用靶向下一代测序技术，我们还有2个正在进行的微生物组项目，以表征人类和/或动物体内不同疾病状态的微生物群体。使用下一代半导体测序仪，通过对肠易激综合征动物模型和人类患者的16 s rRNA区域进行广泛测序来分析微生物组。研究结果在科学会议上作了介绍，并提交出版。另一个微生物组项目最近启动了再生障碍性贫血患者的口腔微生物组。到目前为止，初步的数据分析已经完成，其结果将在IADR会议上公布。将对其他样本进行测序和分析。主要是这两个项目发现，微生物组组成在特定疾病条件下发生变化。为下一代测序仪产生的高通量大数据开发新的分析方法是这些项目的另一个目标。 从这些结果沿着的生物学知识的多个途径的神经系统疾病，我们将能够建议这些疾病的分子遗传机制在个人的水平。最后，我们可以建议综合基因组分析来开发新药，并根据个体遗传信息进行测试。

Most symptoms are multifactorial in origin with both genetic and environmental factors contributing to individual variations. Candidate gene studies on the basis of biological hypotheses have been performed to identify relevant genetic variation in complex traits such as pain. However, the complicated mesh of contributing factors and the thousands of molecules involved in different symptoms makes it difficult to detect responsible genetic variations for an individuals unique susceptibility to disorders. It is unlikely that common variations in a single gene act dominantly on complex traits; rather, the contribution of each gene seems to be subtle, acting on one of multiple biological pathways, making its signal difficult to detect. The combined impact of the rapid increase in knowledge of diseases and the ability to apply powerful and high capacity technology has raised expectations for more effective and safer medicines for various types of symptoms management. Developing new treatment strategies for symptoms management is also critically dependent on identifying new target molecules and defining phenotypes for specific types of disorders. Therefore the first step of this project has been to define the characteristics of experimental and clinical phenotypes. Recently, we launched multiple projects with next generation sequencing (NGS) technology, which allows us to perform entire and/or targeted genome sequencing. The role of genetic and epigenetic factors on symptoms in various disorders and/or conditions will continue to be studied. For example, in neurological disorders such as acute pain, mild traumatic brain injury and PTSD, we are using genotyping, gene and protein expression, and patient reported outcomes to better understand the reciprocal interplay between these factors and the numerous biologic/mechanistic pathways including the inflammatory cascade. Gene expression profiles from the soldiers back from war zone were presented at the multiple meetings (CNRM and ASN meeting) and have been submitted for publication. Two epigenetic studies using DNA methylation chromatin immunoprecipitation followed by whole genome scale sequencing were conducted from civilian and military groups. Epigenetic changes in the sports related concussion patients will be presented at the ASHG meeting. The second epigenetic study in military PTSD patients finished sequencing of samples and the data are under the analysis. Using the targeted next generation sequencing technology, we also have 2 on-going microbiome projects to characterize population of microorganisms in human and/or animal body from different disease status. Using a next generation semiconductor sequencer, microbiome was analyzed with extensive sequencing of 16s rRNA region in an animal model of irritable bowel syndrome and human patients. The results were presented at the scientific meeting and submitted for publication. Another microbiome project was launched recently for oral microbiome from the aplastic anemia patients. So far, preliminary data analysis was finished and its result will be presented at the IADR meeting. Additional samples will be sequenced and analyzed. Mainly both projects found that the microbiome composition is altered in specific disease conditions. Developing new analyzing methods for the high throughput big data generated by the next generation sequencers is another goal of these projects. From these results along with biological knowledge of multiple pathways in neurological disorders, we will be able to suggest molecular-genetic mechanisms of those diseases at the level of the individual. Finally, we can suggest integrative genomic analysis to develop new drugs and test them based on individual genetic information.