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Acutely Induced Insulin Resistance by Antipsychotic Medication in Healthy Volunteers: Impact of Skeletal Muscle Epigenomic and Proteomic Mechanisms

健康志愿者抗精神病药物急性诱导胰岛素抵抗：骨骼肌表观基因组和蛋白质组机制的影响

基本信息

批准号：
10220957
负责人：
Kyle Jon Burghardt
金额：
$ 16.81万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT This K23 Patient-Oriented Mentored Research Award builds on the candidate’s expertise in pharmacology and epigenetics to provide the support necessary to complete training in responsible conduct of research and three other needs: 1) clinical research design and execution, 2) in vivo insulin sensitivity measurement, 3) design and execution proteomics experiments. This training will be accomplished through a combination of expert mentor- ship, didactic (short courses and certificate program) and hands-on experiences (human insulin sensitivity meas- urements and proteomics). The career development activities and research will be mentored by Dr. Zhengping Yi (Primary) and Dr. Renu Kowluru, and supplemented by a physician key collaborator (Dr. Berhane Seyoum), consultants and a yearly, external scientific advisory committee. The candidate’s transition to independence will be aided by an R01 grant writing program, presentation of findings at national conferences and publication of results in high-impact journals. The research plan will provide a platform for training and address a gap in the understanding of how atypical antipsychotics cause insulin resistance. The long-term goal of the proposed work is to establish and sustain an independent career focused on the impact of molecular factors and mechanisms in medication outcomes. The objective is to determine the causal relationship between the observed skeletal muscle epigenetic and protein changes in response to atypical antipsychotics, and the development of insulin resistance using a randomized, placebo-controlled, 7-day trial of olanzapine in healthy volunteers. The central hypothesis, based on preliminary data, is that obesity- and mental illness-independent atypical antipsychotic- induced insulin resistance is caused by DNA hypermethylation and altered protein abundance and regulation in the skeletal muscle. The rationale for this work is that it will establish the molecular mechanisms that underlie atypical antipsychotic-induced insulin resistance, while providing the training and expertise for a research pro- gram to develop precise, tractable targets for future interventions to alleviate epigenetic and/or protein-based dysregulations. The central hypothesis will be tested by obtaining baseline and endpoint basal and insulin-stim- ulated skeletal muscle samples from the 7-day trial in the following specific aims: 1) Identify the relevant genes affected by the hypermethylation seen with atypical antipsychotic-induced insulin resistance and 2) Determine the relevant protein changes underlying obesity-independent atypical antipsychotic-induced insulin resistance. The approach is innovative, in the candidate’s opinion, because it seeks to change the status quo of assessing molecular changes in psychiatric populations already using antipsychotics and because it seeks to assess these changes in a tissue-specific manner using powerful epigenomic and proteomic approaches. The proposed work is significant because it is expected to have a positive impact both on the field, and in positioning the candidate for independence. This work will provide the basis for targeting the molecular dysregulations caused by antipsy- chotics and preventing mortality from insulin resistance and diabetes.

项目概要/摘要 K23 以患者为中心的指导研究奖建立在候选人在药理学和表观遗传学提供必要的支持来完成负责任的研究行为的培训和三个其他需求：1）临床研究设计和执行，2）体内胰岛素敏感性测量，3）设计和执行蛋白质组学实验。该培训将通过专家导师的结合来完成船舶、教学（短期课程和证书课程）和实践经验（人类胰岛素敏感性测量）尿酸盐和蛋白质组学）。职业发展活动和研究将由正平博士指导 Yi（主要）和 Renu Kowluru 博士，并辅以一位医师主要合作者（Berhane Seyoum 博士），顾问和年度外部科学咨询委员会。候选人向独立过渡将得到 R01 资助写作计划、在全国会议上展示研究结果以及出版结果发表在高影响力期刊上。该研究计划将提供一个培训平台并解决了解非典型抗精神病药如何导致胰岛素抵抗。拟议工作的长期目标是建立并维持专注于分子因素和机制影响的独立职业在药物治疗结果中。目的是确定观察到的骨骼之间的因果关系非典型抗精神病药引起的肌肉表观遗传和蛋白质变化以及胰岛素的发展使用奥氮平在健康志愿者中进行的随机、安慰剂对照、为期 7 天的试验来确定耐药性。中央基于初步数据的假设是，与肥胖和精神疾病无关的非典型抗精神病药物诱导的胰岛素抵抗是由 DNA 高甲基化以及蛋白质丰度和调节的改变引起的骨骼肌。这项工作的基本原理是它将建立潜在的分子机制非典型抗精神病药物引起的胰岛素抵抗，同时为研究人员提供培训和专业知识克为未来的干预措施制定精确、易于处理的目标，以减轻表观遗传和/或基于蛋白质的影响失调。将通过获得基线和终点基础和胰岛素刺激来测试中心假设从 7 天的试验中提取骨骼肌样本，其具体目标如下：1) 识别相关基因受非典型抗精神病药物引起的胰岛素抵抗所见的高甲基化的影响，并且 2) 确定与肥胖无关的非典型抗精神病药物引起的胰岛素抵抗的相关蛋白质变化。候选人认为，这种方法是创新的，因为它试图改变评估的现状已经使用抗精神病药物的精神病人群的分子变化，因为它试图评估这些变化使用强大的表观基因组和蛋白质组方法以组织特异性方式发生变化。拟议的工作意义重大，因为预计它将对该领域以及候选人的定位产生积极影响为了独立。这项工作将为针对抗免疫引起的分子失调提供基础胆汁酸并预防胰岛素抵抗和糖尿病造成的死亡。