Adverse Actions of Stimulants on Embryonic Development and Energetics

兴奋剂对胚胎发育和能量的不良作用

• 批准号: 8722152
• 负责人: SHERINE S CHAN
• 金额: $ 29.9万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722152
• 关键词: Adolescent; Adult; Affect; Amphetamines; Animals; Attention deficit hyperactivity disorder; Autophagocytosis; Behavior; Behavioral; Bioenergetics; Biogenesis; Biological Assay; Birth; Breeding; Cardiovascular system; Chemicals; Child; Complex; Congenital Abnormality; Core Facility; Data; Defect; Development; Developmental Process; Elderly; Embryo; Embryonic Development; Energy Metabolism; Exposure to; Genetic; Genus Hippocampus; Glycolysis; Goals; Health; Heart; Homeostasis; Human; Impairment; Knowledge; Laboratories; Life; Long-Term Effects; Measures; Mediating; Metabolism; Methamphetamine; Methodology; Methylphenidate; Mitochondria; Modeling; Monitor; Mothers; Muscle; Nervous system structure; Oxidative Phosphorylation; Oxidative Stress; Pharmaceutical Preparations; Pharmacotherapy; Population; Pregnancy; Prevalence; Process; Proteins; Quality Control; Quality of life; Reactive Oxygen Species; Reporting; Repression; Research; Respiration; Signaling Molecule; Staging; System; Technology; Testing; Time; Tissues; Transgenic Organisms; Work; Zebrafish; aged; behavior test; behavioral impairment; critical period; drug of abuse; high risk sexual behavior; high throughput screening; human tissue; improved; innovation; metabolomics; methamphetamine abuse; methamphetamine exposure; mitochondrial dysfunction; nervous system development; neurobehavioral; novel; postnatal; prenatal; prenatal exposure; prevent; public health relevance; respiratory; stimulant abuse; treatment strategy; zebrafish development

DESCRIPTION (provided by applicant): The long-term goal is to determine how drugs of abuse disrupt mitochondrial energetics and harm embryonic development and health in later life. The timing of embryonic development is highly regulated and coordinated with energy (ATP) metabolism. Preliminary data reveal that inhibition of mitochondrial energetics via genetic means or by exposures to abused drugs cause specific defects in the development of the nervous and cardiovascular systems, which have high energy requirements and are thus dependent on mitochondrial function. Commonly abused ADHD drugs such as methylphenidate (MPH), amphetamine and methamphetamine (METH) impact energy metabolism, as revealed by decreased protein levels of the MRC. However, functional studies to measure respiration have not been performed. Furthermore, the mechanisms by which these drugs impact mitochondrial energetics in embryonic development are elusive. This gap in knowledge is due to the lack of methodology for measuring energetics in developing embryos. The PI's laboratory has developed an innovative high-throughput assay to measure respiration and bioenergetics in zebrafish embryos that takes advantage of the small size of zebrafish embryos, development of embryos outside of the mother, and sheer numbers (100s) of embryos produced by each breeding pair. This assay is indispensable for the proposed studies. The long-term effects of prenatal exposures to MPH or METH are poorly understood. It is important to study, because the lifetime prevalence of illicit METH use in the US population aged 18-49 exceeds 8%, and METH use is associated with risky sexual behavior, pregnancy and persistent behavioral impairments in adulthood. These data, along with our preliminary work leads us to test our central hypothesis: Prenatal exposures to MPH or METH compromise cellular energetics, disrupting the development of tissues that have the highest energetic requirements, resulting in long-term behavioral defects. The rationale for this research is that understanding how mitochondrial dysfunction caused by MPH/METH leads to embryonic defects will guide the development of new treatment strategies to prevent birth defects. This hypothesis will be tested by pursuing two Specific Aims: 1) Determine the mechanism by which MPH or METH exposure disrupts cellular energetics in zebrafish embryos; and 2) Determine the effects of MPH and METH on zebrafish development and behavior. The proposed research is significant, because these studies will elucidate the mechanisms by which prenatal exposures to MPH or METH cause neurobehavioral defects. These zebrafish models can then serve as high-throughput screens for candidate pharmacotherapies that reverse energetic and developmental defects. Preventing birth defects caused by stimulant abuse will vastly improve the quality of life for these children and human health in general.

描述（由申请人提供）：长期目标是确定滥用药物如何破坏线粒体能量学并损害胚胎发育和晚年健康。胚胎发育的时间是高度调节的，并与能量（ATP）代谢协调。初步数据显示，通过遗传手段或通过暴露于滥用药物抑制线粒体能量，导致神经和心血管系统发育的特定缺陷，这些系统具有高能量需求，因此依赖于线粒体功能。经常滥用的ADHD药物，如哌甲酯（MPH），安非他明和甲基安非他明（METH）影响能量代谢，如MRC蛋白质水平降低所揭示的。然而，尚未进行测量呼吸的功能研究。此外，这些药物影响胚胎发育中线粒体能量学的机制尚不清楚。这种知识上的差距是由于缺乏测量胚胎发育中能量学的方法。PI的实验室开发了一种创新的高通量测定方法来测量斑马鱼胚胎的呼吸和生物能量学，该方法利用了斑马鱼胚胎的小尺寸，胚胎在母体外的发育以及每个繁殖对产生的胚胎数量（100个）。该测定对于拟定研究是必不可少的。产前暴露于MPH或METH的长期影响知之甚少。研究很重要，因为美国18-49岁人口中非法使用METH的终生流行率超过8%，并且METH的使用与危险性行为，怀孕和成年后持续的行为障碍有关。这些数据，沿着我们的初步工作，使我们能够验证我们的核心假设：产前暴露于MPH或METH会损害细胞能量，破坏具有最高能量需求的组织的发育，导致长期的行为缺陷。这项研究的基本原理是，了解MPH/METH引起的线粒体功能障碍如何导致胚胎缺陷，将指导新的治疗策略的开发，以预防出生缺陷。这一假设将通过追求两个具体目标进行测试：1）确定MPH或METH暴露破坏斑马鱼胚胎细胞能量学的机制; 2）确定MPH和METH对斑马鱼发育和行为的影响。这项拟议的研究意义重大，因为这些研究将阐明产前暴露于MPH或METH导致神经行为缺陷的机制。然后，这些斑马鱼模型可以作为高通量筛选候选药物疗法，逆转能量和发育缺陷。预防兴奋剂滥用导致的出生缺陷将大大改善这些儿童的生活质量和人类的整体健康。