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

• 批准号: 9750240
• 负责人: Kyle Jon Burghardt
• 金额: $ 16.84万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750240
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Address; Advisory Committees; Affect; Aftercare; Antipsychotic Agents; Award; Biopsy; Bipolar Disorder; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinical Research; Comorbidity; Cyclic AMP-Dependent Protein Kinases; DNA; DNA Methylation; Data; Development; Diabetes Mellitus; Drug usage; Epigenetic Process; Future; Gene Proteins; Genes; Goals; Grant; Healthy People 2020; Human; Hypermethylation; Insulin Resistance; Intervention; Journals; Knowledge; Life Expectancy; Link; Measurement; Mental disorders; Mentors; Mentorship; Metabolic syndrome; Mission; Modification; Molecular; Molecular Target; Obesity; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacy facility; Physicians; Placebos; Population; Positioning Attribute; Proteins; Proteomics; Psychiatric therapeutic procedure; Public Health; Publications; Randomized; Regulation; Research; Research Design; Resistance; Risk; Sampling; Schizophrenia; Skeletal Muscle; Testing; Time; Tissues; Training; Treatment outcome; United States National Institutes of Health; Weight Gain; Work; Writing; atypical antipsychotic; basal insulin; base; cardiometabolism; career; career development; certificate program; design; disability; epigenomics; experience; experimental study; glucose disposal; healthy volunteer; in vivo; innovation; insulin sensitivity; mortality; olanzapine; patient oriented; prevent; programs; response; responsible research conduct; side effect; skills; symposium

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.

项目总结/摘要 这个K23以患者为导向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，以完成负责任的研究行为的培训， 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。这一培训将通过专家导师的组合来完成， 船舶，教学（短期课程和证书课程）和实践经验（人胰岛素敏感性测量， 测量和蛋白质组学）。职业发展活动和研究将由Zhengping博士指导 Yi（主要）和Renu Kowluru博士，并由一名医生主要合作者（Berhane Seyoum博士）补充， 顾问和每年一次的外部科学咨询委员会。候选人向独立的过渡将 通过R 01资助写作计划，在全国会议上介绍研究结果和出版 在高影响力的期刊上发表。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物如何导致胰岛素抵抗。拟议工作的长期目标 建立和维持一个独立的职业生涯，专注于分子因素和机制的影响 药物治疗的结果。目的是确定所观察到的骨骼 肌肉表观遗传和蛋白质变化对非典型抗精神病药物的反应，以及胰岛素的发展 在健康志愿者中进行的一项为期7天的奥氮平随机、安慰剂对照试验。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， 诱导的胰岛素抵抗是由DNA超甲基化和改变的蛋白质丰度和调节引起的， 骨骼肌这项工作的基本原理是，它将建立分子机制， 非典型抗精神病药诱导的胰岛素抵抗，同时为研究专家提供培训和专业知识， gram开发精确，易于处理的目标，用于未来的干预措施，以减轻表观遗传和/或蛋白质为基础的 失调将通过获得基线和终点基础胰岛素和胰岛素刺激来检验中心假设。 来自7天试验的骨骼肌样品在以下特定目的中：1）鉴定相关基因 受非典型抗精神病药诱导的胰岛素抵抗的高甲基化影响，2）确定 相关蛋白质的变化是肥胖非依赖性非典型抗精神病药诱导的胰岛素抵抗的基础。 在候选人看来，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学和蛋白质组学方法以组织特异性方式进行变化。拟议工作 重要的是，它预计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药引起的分子失调提供基础。 chotics和预防胰岛素抵抗和糖尿病的死亡率。