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: 9253833
• 负责人: Vivian K Kawai
• 金额: $ 11.92万
• 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/9253833
• 关键词: Pharmacogenetic; Determinants; Variability; Response; Glucocorticoids

 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（由申请人提供）此K23提案将帮助候选人实现她的长期职业目标，成为临床药理学领域的独立学术研究人员，主要关注药物遗传学。实现这一目标的直接步骤包括获得遗传学方面的额外培训，制定指导其职业发展的全面导师计划，以及执行一个创新研究项目，旨在提供候选人所需技能的实践培训，以促进其向独立过渡。因此，这个K23建议有三个主要组成部分：首先，候选人，一个人谁拥有医学博士和公共卫生硕士学位，并作出了认真的承诺，以病人为导向的研究学术生涯，但缺乏遗传学技能。第二，职业发展计划，旨在为候选人提供指导和关键技能，在新的领域，她，但她的发展是必要的：遗传流行病学，生物信息学和先进的统计。第三，一个研究项目，整合了严格的培训和指导研究，以解决一个重要的科学问题：糖皮质激素（GC）的疗效和毒性的变异性背后的遗传机制是什么？GC是用于治疗常见疾病的强效抗炎和免疫抑制药物，包括几种危及生命和器官的疾病。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反应的巨大个体间变异性具有遗传成分，但这种变异性的遗传决定因素仍然未知。这项拟定研究将使用两种相关GC相关表型定义GC疗效和毒性变异性的遗传贡献：GC诱导的淋巴细胞减少症（一种成熟、经验证的GC效应药效学指标）和GC诱导的葡萄糖耐受不良（GC治疗的一种重要副作用）。因此，我们提出了三个具体目标：1）使用全基因组方法，以GC诱导的淋巴细胞减少症为表型，鉴定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诱导的葡萄糖耐受不良风险的联合作用;和3）在健康受试者中使用GC诱发的反应验证与GC诱导的淋巴细胞减少症和葡萄糖耐受不良相关的遗传变异。对于前两个具体目标，我们将使用范德比尔特的DNA库（BioVU），这是最大的基于临床实践的生物库，与去识别的电子医疗记录副本相关联。在目标3中，我们将通过在良好控制的环境中研究这些表型，用单剂量GC挑战健康个体，最大限度地减少GC反应中混杂因素的影响。候选人的发展是通过范德比尔特大学的支持性环境培养的，范德比尔特大学拥有独特的资源来进行计算机模拟和体内人体药理学和药物遗传学研究。她的导师Michael Stein博士和Nancy考克斯博士是资深研究人员，拥有长期的NIH资助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，并承诺投入时间和资源来培训和帮助她。这沿着拟议的培训计划和项目的优势，将确保候选人成功成为一名独立的学术研究人员。