Pharmacogenetic Determinants of Variability in Response to Glucocorticoids

糖皮质激素反应变异性的药物遗传学决定因素

• 批准号: 9322495
• 负责人: Vivian K Kawai
• 金额: $ 18.41万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-20 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322495
• 关键词: Address; Adverse effects; Adverse event; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Area; Asthma; Beta Cell; Bioinformatics; Caring; Clinical; Clinical Pharmacology; Complication; Computer Simulation; Computerized Medical Record; Controlled Environment; DNA; DNA Library; Data; Development; Development Plans; Diabetes Mellitus; Disease; Doctor of Medicine; Dose; Drug usage; Ensure; Frequencies; Functional disorder; Funding; Future; Gene Expression Profiling; General Population; Genetic; Genetic Determinism; Genetic Transcription; Genetic study; Glucocorticoids; Glucose Intolerance; Goals; Human; Hyperglycemia; Immunosuppressive Agents; Impairment; Individual; Inflammation; Inflammatory Bowel Diseases; Insulin Resistance; Kinetics; Life; Link; Lymphocyte; Master of Public Health; Measurement; Measures; Mentors; Mentorship; Metabolic; Metabolic Diseases; Modeling; Molecular; Organ; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology; Phenotype; Play; Prednisone; Prospective Studies; Reproducibility; Research; Research Personnel; Research Project Grants; Resources; Risk; Role; Savings; Severities; Signal Transduction; Testing; Therapeutic Glucocorticoid; Time; Toxic effect; Training; Training Programs; Treatment Efficacy; Treatment Failure; United States National Institutes of Health; Universities; base; biobank; blood glucose regulation; career; career development; clinical practice; cohort; collaborative environment; design; disease heterogeneity; genetic epidemiology; genetic predictors; genetic variant; genome wide association study; genome-wide; glucose metabolism; improved; in vivo; innovation; patient oriented research; pharmacodynamic model; pharmacokinetic model; public health relevance; response; skills; statistics; success; training project; treatment response

 DESCRIPTION (provided by applicant) This K23 proposal will assist the candidate to achieve her long-term career goal of becoming an independent academic researcher in the field of clinical pharmacology with a primary focus in pharmacogenetics. The immediate steps to reach this goal include obtaining additional training in genetics, establishing a comprehensive mentorship plan that will guide her career development, and the performance of an innovative research project designed to provide hands-on training in the skills the candidate needs to develop to facilitate her transition to independence. Thus, this K23 proposal has three major components: First, the candidate, an individual who has Doctor of Medicine and Master of Public Health degrees and has made serious commitments to an academic career in patient-oriented research but lacks skills in genetics. Second, a career development plan designed to provide the candidate with mentoring and critical skills in areas new to her but necessary for her development: genetic epidemiology, bioinformatics and advanced statistics. Third, a research project that integrates rigorous training and mentored research to address an important scientific question: What are the genetic mechanisms underlying variability in the efficacy and toxicity of glucocorticoids (GCs)? GCs are potent anti-inflammatory and immunosuppressant drugs used to treat common illnesses, including several life- and organ-threatening diseases. Despite their frequent use, there is large variability in efficacy and toxicity that results in inadequate therapeutic responses and GC-induced metabolic side effects. The large inter-individual variability in GC response has a genetic component, but the genetic determinants of this variability remain unknown. This proposed research would define the genetic contributions to variability in GC efficacy and toxicity using two relevant GC-related phenotypes: GC-induced lymphopenia (a well- established, validated pharmacodynamic measure of GC effect) and GC-induced glucose intolerance (an important side effect of GC therapy). Thus, we propose three Specific Aims: 1) identify the genetic determinants of GC efficacy using GC-induced lymphopenia as a phenotype using a genome-wide approach; 2) determine the combined effects of genetic variants known to be associated with glucose homeostasis on the risk of GC-induced glucose intolerance; and 3) validate the genetic variants associated with GC-induced lymphopenia and glucose intolerance using GC-evoked responses in healthy subjects. For the first two specific aims we will use Vanderbilt's DNA bank (BioVU) the largest clinical practice-based biobank linked to de- identified copies of electronic medical records. In aim 3 we will minimize the effects of confounders in GC response by studying these phenotypes in a well-controlled environment by challenging healthy individuals with a single dose of GC. The candidate's development is nurtured through a supportive environment at Vanderbilt University, which has unique resources to perform in silico and in vivo human pharmacology and pharmacogenetic studies. Her mentors, Dr. Michael Stein and Dr. Nancy Cox, are well-established senior investigators with longstanding NIH funding and outstanding expertise in clinical pharmacology and pharmacogenetics. They strongly support the candidate's career plan and have committed time and resources to train and assist her. This, along with the strengths of the proposed training program and project, will ensure the candidate's success in becoming an independent academic researcher.

 描述(申请人提供)这份K23提案将帮助应聘者实现她的长期职业目标，即成为临床药理学领域的独立学术研究人员，主要专注于药物遗传学。实现这一目标的直接步骤包括获得额外的遗传学培训，建立一个全面的导师计划来指导她的职业发展，以及执行一个创新的研究项目，旨在提供候选人需要发展的技能的动手培训，以促进她向独立的过渡。因此，这份K23提案有三个主要组成部分：第一，候选人，拥有医学博士和公共卫生硕士学位，并认真致力于以患者为中心的研究的学术生涯，但缺乏遗传学技能。第二，职业发展计划，旨在为应聘者提供新领域的指导和关键技能，这些领域对她的发展是必要的：遗传流行病学、生物信息学和高级统计学。第三，一个整合了严格培训和指导研究的研究项目，以解决一个重要的科学问题：糖皮质激素(GC)疗效和毒性变异背后的遗传机制是什么？GCS是一种有效的抗炎和免疫抑制药物，用于治疗常见疾病，包括几种威胁生命和器官的疾病。尽管它们经常使用，但在疗效和毒性方面存在很大的差异，导致治疗反应不足和GC诱导的代谢副作用。GC反应中巨大的个体间变异性有遗传成分，但这种变异性的遗传决定因素尚不清楚。这项拟议的研究将使用两种与GC相关的表型来确定遗传因素对GC疗效和毒性变化的影响：GC诱导的淋巴细胞减少(GC效应的一个公认的、经过验证的药效学指标)和GC诱导的葡萄糖耐量(GC治疗的一个重要副作用)。因此，我们提出了三个具体目标：1)使用全基因组方法，确定GC疗效的遗传决定因素；2)确定已知与葡萄糖稳态相关的遗传变异对GC诱导的葡萄糖耐受风险的综合影响；以及3)利用GC诱发的反应，在健康受试者中验证与GC诱导的淋巴细胞减少和葡萄糖耐受相关的遗传变异。对于前两个具体目标，我们将使用Vanderbilt的DNA库(BioVU)，这是一个最大的基于临床实践的生物库，与未识别的电子医疗记录副本相关联。在目标3中，我们将最大限度地减少混杂因素在GC反应中的影响，方法是在受控良好的环境中研究这些表型，用单剂量GC挑战健康人。候选人的发展是通过范德比尔特大学的支持性环境来培养的，范德比尔特大学在硅胶和活体人类药理学和药物遗传学研究方面拥有独特的资源。她的导师迈克尔·斯坦博士和南希·考克斯博士都是久负盛名的高级研究人员，拥有NIH长期资助的资金和临床药理学和药物遗传学方面的杰出专业知识。他们强烈支持候选人的职业规划，并投入时间和资源对她进行培训和协助。这一点，加上拟议的培训计划和项目的优势，将确保候选人成功地成为一名独立的学术研究人员。