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: 8735582
• 负责人: Ann Cashion
• 金额: $ 61.88万
• 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/8735582
• 关键词: Absence of pain sensation; Acute; Acute Pain; American; Analgesics; Back; Biological; Biological Assay; Cancer Fatigue; Candidate Disease Gene; Capsaicin; Cerebrovascular Spasm; Characteristics; Chronic; Clinical; Clinical Research; Complex; Data; Disease; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Ethnic Origin; Fibromyalgia; Gender; Gene Expression; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Hemorrhage; Human Genetics; Human Genome; Human body; Individual; Inflammatory; Injury; International; Investigation; Knowledge; Medicine; Methods; Molecular Genetics; Molecular Profiling; Neurologic; Nucleotides; Pain; Pathway interactions; Patient Outcomes Assessments; Patients; Phantom Limb Pain; Pharmacogenomics; Phenotype; Population; Post-Traumatic Stress Disorders; Predisposition; Psychological Factors; Publishing; Reporting; Role; SNP genotyping; Science; Series; Services; Signal Transduction; Societies; Soldier; Stroke; Symptoms; Technology; Testing; Therapeutic Intervention; Time; Tissues; Traumatic Brain Injury; Variant; War; acute coronary syndrome; base; biobehavior; clinical phenotype; combat; drug testing; environmental change; expectation; functional genomics; genetic association; genome sequencing; genome wide association study; meetings; member; microbiome; microorganism; nervous system disorder; next generation; next generation sequencing; novel; protein expression; response; symposium; symptom management; 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. Contributing factors such as gender, ethnicity and psychological factors predominate over the role of genetic factors in pain and analgesic responses when evaluating groups of patients (Kim et al. 2004a; Kim et al. 2004b). But genetic variability may be important at the level of the individual (Dionne et al. 2005). We published a whole genome scan study related to clinical symptoms using 500,000 SNPs assay in the clinical symptoms(Kim et al. 2009, Pharmacogenomics). We have expanded the number of testing SNPs up to 1 million from human genome and are genotyping hundreds of patients with fibromyalgia, acute coronary syndrome and subarrachnoid hemorrhage. Results from those studies were reported at the annual meetings of American Pain Society, American Society of Human Genetics and International Stroke Conference. Detailed information and functional genomic studies of the candidate regions from those projects may provide knowledge for the genetic role in responses to tissue injury, pain and analgesia and other neurological symptoms on an individual patient basis. Also the result of genetic association in the evidence of cerebral vasospasm based on transcranial doppler signals in subarrachnoid hemorrhage patients was publishced in 2012 (Kim et al. 2012, Int J of Stroke). Same technology has been applied to investigate the association for the PTSD and phantom limb pain from service members returned from war zone. Recently, we launched projects with next generation sequencing technology, which allows us perform entire genome sequencing for individuals with unique phenotypes such as capsaicin non-sensitive patients, and epigenetic changes following long term environmental changes such as soldiers exposed to combat, and traumatic brain injury resulted to the post traumatic stress disorder. The role of genetic and epigenetic factors on clinical pain will continue to be studied in neurological disorders such as acute pain and PTSD using genotyping, gene and protein expression, and patient reported outcomes to better understand the reciprocal interplay between these factors and the inflammatory cascade. These data will be analyzed with whole genome sequencing, microarray, ELISA, SNP genotyping, and real time PCR. Gene expression profiles from the soldiers back from war zone were presented at the multiple meetings (CNRM and ASN meeting). Epigeetic changes in the cancer fatigue patients will also be presented at the ASHG meeting this year. Using the next generation sequencing technology, we also launched microbiome projects to characterize population of microorganisms in human body. Developing new analyzing methods for the high throughput 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.

大多数症状是由多因素引起的，遗传和环境因素都会导致个体差异。在生物学假说的基础上进行了候选基因研究，以确定疼痛等复杂特征的相关遗传变异。然而，复杂的致病因素和涉及不同症状的数千个分子，使得很难检测到一个独特的疾病易感性个体的负责任的基因变异。单个基因中常见的变异不太可能主要作用于复杂的特征；相反，每个基因的贡献似乎很微妙，作用于多个生物途径中的一个，使其信号很难被检测到。 疾病知识的迅速增加以及应用强大和高容量技术的能力的共同影响，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。为症状管理开发新的治疗策略也严重依赖于识别新的靶分子和确定特定类型疾病的表型。因此，这个项目的第一步是确定实验和临床表型的特征。在评估患者组时，性别、种族和心理因素等促成因素在疼痛和止痛反应中的作用超过遗传因素(Kim等人。2004a；Kim等人。2004b)。但遗传变异在个体水平上可能是重要的(Dionne等人。2005)。 我们发表了一项与临床症状相关的全基因组扫描研究，使用了500,000个SNPs分析临床症状(Kim等人。2009年，药物基因组学)。我们已经将检测人类基因组的SNPs的数量扩大到100万个，并正在对数百名患有纤维肌痛、急性冠脉综合征和蛛网膜下腔出血的患者进行基因分型。这些研究的结果发表在美国疼痛学会、美国人类遗传学学会和国际中风会议的年度会议上。来自这些项目的候选区域的详细信息和功能基因组研究可能提供关于个体患者在对组织损伤、疼痛和止痛以及其他神经症状的反应中的遗传作用的知识。此外，基于蛛网膜下腔出血患者经颅多普勒信号的脑血管痉挛证据的遗传关联结果也于2012年发表(Kim等人。2012年，Int J of Stroke)。同样的技术也被应用于研究从战区归来的军人的创伤后应激障碍和幻肢疼痛之间的联系。 最近，我们启动了使用下一代测序技术的项目，该技术允许我们对具有独特表型的个人进行全基因组测序，例如辣椒素不敏感的患者，以及长期环境变化后的表观遗传变化，例如士兵暴露在战斗中，以及创伤后应激障碍导致的创伤性脑损伤。遗传和表观遗传因素在临床疼痛中的作用将继续在神经疾病中进行研究，如急性疼痛和创伤后应激障碍，使用基因分型、基因和蛋白表达以及患者报告的结果，以更好地了解这些因素和炎症级联反应之间的相互作用。这些数据将通过全基因组测序、微阵列、酶联免疫吸附试验、SNP基因分型和实时聚合酶链式反应进行分析。从战区返回的士兵的基因表达谱在多次会议(CNRM和ASN会议)上公布。癌症疲劳患者的警示变化也将在今年的ASHG会议上公布。利用下一代测序技术，我们还启动了微生物组项目，以表征人体内的微生物种群。为下一代测序仪产生的高通量数据开发新的分析方法是这些项目的另一个目标。 根据这些结果以及神经系统疾病中多个途径的生物学知识，我们将能够在个体水平上提出这些疾病的分子遗传机制。最后，我们可以建议进行综合基因组分析来开发新药，并基于个人遗传信息对其进行测试。