Genome-wide interrogation of genetic signatures for glucocorticoid sensitivity

对糖皮质激素敏感性遗传特征进行全基因组询问

• 批准号: 7771932
• 负责人: Rong Stephanie Huang
• 金额: $ 9.73万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7771932
• 关键词: Adverse event; Advisory Committees; Affect; Age; Airway Resistance; Allergic; Arthritis; Asthma; Autoimmune Diseases; Award; Bioinformatics; Biological Assay; Candidate Disease Gene; Caring; Cell Cycle Arrest; Childhood Asthma; Clinical; Clinical Pharmacology; Clinical Trials; Clinical Trials Design; Correlation Studies; Data; Development; Dexamethasone; Disease; Enrollment; Enzyme-Linked Immunosorbent Assay; Epidemiology; Fellowship; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glucocorticoid Receptor; Glucocorticoids; Goals; Growth; Human; Human Genome; Immunosuppression; In Vitro; Individual; Individual Differences; Inflammatory; Inflammatory Bowel Diseases; Inhibition of Apoptosis; International; Knowledge; Laboratories; Maintenance; Mentors; Modeling; Molecular Profiling; Other Genetics; Outcome; Pathway interactions; Patient Care; Patients; Pharmacogenetics; Pharmacogenomics; Pharmacy Schools; Phase I Clinical Trials; Phenotype; Play; Predisposition; Quality of life; Race; Research; Research Personnel; Risk; Role; Sampling; Single Nucleotide Polymorphism; System; Systems Biology; Testing; Therapeutic; Toxic effect; Training; Translations; Transplant Recipients; Work; career; career development; cell growth; chemotherapeutic agent; chemotherapy; cytotoxicity; design; drug sensitivity; follow-up; genetic variant; genome wide association study; genome-wide; improved; lymphoblastoid cell line; mRNA Expression; novel; programs; prospective; public health relevance; response; treatment effect

DESCRIPTION (provided by applicant): The principle investigator's career goal is to be a successful translational researcher in the field of Clinical Pharmacology. With this Award, she plans to further her training in systems biology, statistical genetics and bioinformatics. She proposes to extend a genome-wide model developed during her fellowship to broader therapeutic application beyond chemotherapy and validate her findings in patient samples. The PI's long-term goal is to combine her patient care knowledge from Pharmacy school and research knowledge through her work in Pharmacogenetics to eventually improve the quality of life for patients. Dr. Eileen Dolan (Internationally recognized researcher in pharmacogenomics) will serve as the PI's main mentor; while Drs. Nancy Cox (internationally recognized statistical geneticist) and Mark Ratain (internationally recognized leader in pharmacogenetics and phase I trial design) will co-mentor the PI's scientific and career development. Her advisory committee consists of Drs. Scott Weiss, Julian Solway and Kelan Tantisira, who will provide scientific guidance in utilizing patient samples in studying pharmacogenomics markers for glucocorticoid (GC) sensitivity in asthma. An objective of this proposal is to take a concerted translational effort to elucidate the underlying cause for the inter-individual differences in sensitivity to GCs, one of the most commonly used agents in treating inflammatory diseases such as asthma, inflammatory bowel disease and arthritis. Our hypothesis is that a novel genome-wide model developed using International HapMap lymphoblastoid cell lines (LCLs) are suitable in identification of genetic polymorphisms as predictors of cellular sensitivity to GCs. Our specific aims are 1) To develop and refine GC sensitivity phenotypic assays to quantify in vitro GC response and toxicity; 2) To identify genetic polymorphisms that are associated with GC susceptibility phenotypes through gene expression; 3) To validate candidate genetic variants/genes in patient samples. Our long-term goal is to predict patients "at risk" for adverse events and/or non-response prior to administration of GCs. PUBLIC HEALTH RELEVANCE: This proposal is intended to better understand how genetic variation contributes to individual sensitivity to GCs. The long term goal is to identify patients, using their genetic make up, that are at risk for toxicities and non- response associated with GCs with the intent to reduce their chances of an adverse event and improve their care.

描述(申请人提供)：首席研究员的职业目标是成为临床药理学领域的一名成功的翻译研究员。有了这个奖项，她计划进一步在系统生物学、统计遗传学和生物信息学方面进行培训。她建议将她在研究员期间开发的全基因组模型扩展到化疗以外的更广泛的治疗应用，并在患者样本中验证她的发现。PI的长期目标是将她在药学院学习的患者护理知识与她在药物遗传学工作中的研究知识结合起来，最终提高患者的生活质量。艾琳·多兰博士(国际公认的药物基因组学研究人员)将担任该协会的主要导师，而南希·考克斯博士(国际公认的统计遗传学家)和马克·拉坦博士(国际公认的药物遗传学和I期试验设计的领导者)将共同指导该协会的科学和事业发展。她的顾问委员会由Scott Weiss博士、Julian Solway博士和Kelan Tantisira博士组成，他们将为利用患者样本研究哮喘患者糖皮质激素(GC)敏感性的药物基因组学标记提供科学指导。这项建议的一个目的是采取协调一致的翻译努力，以阐明个体之间对GCs敏感性差异的根本原因，GCs是治疗哮喘、炎症性肠病和关节炎等炎症性疾病的最常用药物之一。我们的假设是，利用国际HapMap淋巴母细胞系(LCLS)开发的一种新的全基因组模型适合于识别基因多态作为细胞对GCs敏感性的预测因子。我们的具体目标是1)发展和完善GC敏感性表型分析，以量化体外GC反应和毒性；2)通过基因表达确定与GC易感性表型相关的遗传多态；3)在患者样本中验证候选遗传变异/基因。我们的长期目标是在服用GCs之前预测患者的不良事件和/或无反应的“风险”。 公共卫生相关性：这项建议旨在更好地了解基因变异如何导致个体对GCs的敏感性。长期目标是利用他们的基因构成识别与GCs相关的毒性和无反应风险的患者，以降低他们发生不良事件的机会并改善他们的护理。