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

项目摘要/摘要 这项以患者为导向的K23指导性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，以完成负责任的研究和三项培训 其他需求：1)临床研究设计和实施，2)体内胰岛素敏感性测量，3)设计和实施 执行蛋白质组学实验。这项培训将通过专家导师的组合完成- 培训、授课(短期课程和证书计划)和实践经验(人类胰岛素敏感性测量- 尿路和蛋白质组学)。职业发展活动和研究将由正平博士指导 Yi(小学)和Renu Koluru博士，并由一名内科主要合作者(Berhane Seyoum博士)补充， 顾问和每年一度的外部科学咨询委员会。这位候选人向独立的过渡将 由R01赠款编写方案、在国家会议上提交调查结果和出版 结果发表在影响力很大的期刊上。该研究计划将为培训提供一个平台，并解决 了解非典型抗精神病药物如何导致胰岛素抵抗。拟议工作的长期目标 是建立和维持一个独立的职业，专注于分子因素和机制的影响 在用药结果上。目的是确定观察到的骨骼之间的因果关系 非典型抗精神病药物对肌肉表观遗传学和蛋白质的影响，以及胰岛素的发展 在健康志愿者中使用随机、安慰剂对照、为期7天的奥氮平试验进行耐药性研究。中环 基于初步数据的假设是，肥胖和精神疾病非典型抗精神病药物- 诱导的胰岛素抵抗是由DNA超甲基化和蛋白丰度和调控改变引起的 骨骼肌。这项工作的基本原理是，它将建立作为基础的分子机制 非典型抗精神病药物诱导的胰岛素抵抗，同时为一项研究提供培训和专业知识 葛兰素史克为未来的干预制定精确、易处理的目标，以减轻表观遗传和/或基于蛋白质的影响 不规范。将通过获得基线和终点基础和胰岛素刺激来检验中心假设。 来自7天试验的模拟骨骼肌样本的具体目的如下：1)识别相关基因 受非典型抗精神病药物诱导的胰岛素抵抗的高甲基化的影响和2)确定 肥胖非典型抗精神病药物诱导的胰岛素抵抗背后的相关蛋白质变化。 在候选人看来，这种方法是创新的，因为它寻求改变评估的现状 已经使用抗精神病药物的精神病患者的分子变化，因为它试图评估这些 使用强大的表观基因组学和蛋白质组学方法，以组织特有的方式进行变化。拟议中的工作 意义重大，因为预计它将对现场和候选人的定位产生积极影响 为了独立。这项工作将为靶向抗精神病所致的分子失调奠定基础。 选择和预防因胰岛素抵抗和糖尿病而死亡。

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.