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: 9978821
• 负责人: Kyle Jon Burghardt
• 金额: $ 16.86万
• 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/9978821
• 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; 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; comorbidity; 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/文摘