Genomic Analyses for Elucidating Novel Targets for Symptoms Management

用于阐明症状管理新目标的基因组分析

• 批准号: 9148043
• 负责人: Ann Cashion
• 金额: $ 81.16万
• 依托单位: NATIONAL INSTITUTE OF NURSING RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9148043
• 关键词: Acute; Acute Pain; Animal Model; Animals; Aplastic Anemia; Back; Behavioral; Big Data; Biological; Biological Assay; Brain Concussion; Candidate Disease Gene; Characteristics; Chronic; Clinical Research; Complex; DNA; DNA Methylation; Data Analyses; Disease; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Human; Individual; Inflammatory; Investigation; Irritable Bowel Syndrome; Knowledge; Measurement; Measures; Medicine; Methods; MicroRNAs; Military Personnel; Molecular Genetics; Molecular Profiling; Neurologic; Pain; Pathway interactions; Patient Outcomes Assessments; Patients; Phenotype; Plasma; Population; Post-Traumatic Stress Disorders; Predisposition; Protein Analysis; Proteins; Publications; Publishing; RNA; RNA analysis; Ribosomal RNA; Role; Sample Size; Sampling; Science; Semiconductors; Sensory Disorders; Series; Siblings; Signal Transduction; Single Nucleotide Polymorphism; Sleep disturbances; Soldier; Sports; Symptoms; Technology; Therapeutic Intervention; Untranslated RNA; Variant; War; base; chromatin immunoprecipitation; clinical phenotype; drug testing; expectation; genetic information; genome sequencing; genome-wide; meetings; microbiome; microorganism; mild traumatic brain injury; nervous system disorder; next generation; next generation sequencing; non-genomic; novel; oral microbiome; protein expression; sample collection; symptom management; targeted sequencing; tau Proteins; trait; translational study; treatment strategy

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 published. We also started SNP assays and micro RNA analysis from similar samples from war zone soldiers. The results were also presented at multiple meetings and published. 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 was presented at the ASHG meeting. This result was submitted for publication and currently under review. The second epigenetic study in military PTSD patients finished sequencing of first set of samples. After the primary data analysis, we increased sample size and will sequence more. Whole genome sequencing of special sensory disorder patient and control sibling were sequenced and will be analyzed. 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 for oral microbiome from the aplastic anemia patients was also on-going and finished the sample collection. So far, preliminary data analysis was finished and its result was presented at the IADR meeting and submitted for publication. Mainly both projects found that the microbiome composition is altered in specific disease conditions. Considering that the protein is the final product from DNA and RNA, protein analysis from those multiple projects has been recently launched. We especially focus on proteins showing trace amount only so that it makes difficult to detect with conventional protein assays such as ELISA. So far, we have successfully detect tau protein in plasma, which has not been measured with ELISA. Developing new analyzing methods for the high throughput big data generated by the next generation sequencers including whole genome sequencing, gene expression signatures, epigenetics and their interactions with other factors such as proteins and environment factors 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.

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。单个基因的共同变异不太可能对复杂性状起主导作用;相反，每个基因的作用似乎很微妙，作用于多个生物途径中的一个，使其信号难以检测。 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。 从战区返回的士兵的基因表达谱在多个会议（CNRM和ESTA会议）上提出，并已发表。我们还开始从战区士兵的类似样本中进行SNP分析和微RNA分析。研究结果还在多次会议上介绍并发表。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。 在ASHG会议上介绍了运动相关脑震荡患者的表观遗传变化。这一结果已提交出版，目前正在审查中。第二项对军人PTSD患者的表观遗传学研究完成了第一组样本的测序。初步数据分析后，我们增加了样本量，并将对更多样本进行测序。 对特殊感觉障碍患者和对照同胞的全基因组测序并进行分析。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种群。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。再生障碍性贫血患者口腔微生物组的另一个微生物组项目也在进行中，并完成了样本收集。到目前为止，初步数据分析已经完成，其结果已提交给IADR会议并提交出版。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。 考虑到蛋白质是DNA和RNA的最终产物，最近启动了对这些多个项目的蛋白质分析。我们特别关注仅显示痕量的蛋白质，使得难以用常规蛋白质测定法如ELISA检测。到目前为止，我们已经成功地检测到血浆中的tau蛋白，这还没有用ELISA测量。 这些项目的另一个目标是为下一代测序仪产生的高通量大数据开发新的分析方法，包括全基因组测序，基因表达特征，表观遗传学及其与蛋白质和环境因素等其他因素的相互作用。 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。