Behavioral and Molecular Effects of Antenatal SSRI Exposure

产前 SSRI 暴露对行为和分子的影响

基本信息

批准号：
8425353
负责人：
LAWRENCE S QUANG
金额：
$ 18.04万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-15 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8425353
关键词：
1 year old Address Adult Advisory Committees Animals Antidepressive Agents Behavior Behavioral Behavioral Assay Behavioral Genetics Behavioral Model Biological Assay Boston Brain Child Childhood Clinical Research Cognitive Collaborations Complement Development Elderly Embryo Emergency Medicine Emotional Emotions Environmental Health Exposure to Fellowship Fluorescence-Activated Cell Sorting Fluoxetine Future Gene Expression Genes Genetic Genetic Research Genome In Situ Hybridization Lead Learning Life Long-Term Effects Longevity Medical Mental Depression Mental Health Mentors Michigan Molecular Molecular Genetics Molecular Profiling Mood Disorders Mouse Protein Mus Neurons Neurosciences Neurotransmitters Nucleic Acid Regulatory Sequences Pathogenesis Pediatric Hospitals Pediatrics Perinatal Exposure Pharmaceutical Preparations Phenotype Postdoctoral Fellow Predisposition Pregnancy Pregnant Women Principal Investigator Proteins Publishing Reporting Research Research Personnel Residencies Rodent Selective Serotonin Reuptake Inhibitor Serotonin Staging System Systems Development Techniques Testing To specify Toxicology Training Training Activity Training Programs Transgenic Mice Transgenic Organisms Universities Uterus career career development early childhood experience fetal graduate student hindbrain in vivo innovation interest maternal depression medical schools mouse nonagouti protein neurobehavioral neuron development offspring pregnant professor programs public health relevance research study skills tool transcription factor transgene expression

项目摘要

DESCRIPTION (provided by applicant): This application describes a 4-year training program for an academic career in pediatrics. The Principal Investigator (Principal Investigator) has completed residency training in pediatrics at Children's Hospital of Michigan/Wayne State University School of Medicine and fellowship training in both pediatric emergency medicine and medical toxicology at Children's Hospital of Boston/Harvard Medical School. He will now expand upon his scientific skills through a unique inter-departmental collaboration between the Department of Neurosciences and the Departments of Environmental Health Sciences and Pediatrics, the Principal Investigator's primary and secondary departments, respectively, at Case Western Reserve University (CWRU). The inter-departmental collaboration will provide the Principal Investigator with mentored research, career development, and training activities for a future career as an independent investigator. This program will promote the command of the regulatory programs that govern the development of the vertebrate serotonin (5-HT) system, and its condition after perturbation with antenatal Selective Serotonin Reuptake Inhibitor (SSRI) exposure. Dr. Evan Deneris will mentor the Principal Investigator's scientific development and is a recognized leader in the field of molecular genetics of the brain 5-HT neurotransmitter system. He has made fundamental contributions to the understanding of the genetic mechanisms that act across the lifespan to regulate 5-HT system function and how these mechanisms impact 5-HT modulated behaviors. His studies have identified the Pet-1 transcription factor that functions in an embryonic regulatory network to specify 5-HT neurons in the mouse ventral hindbrain. Dr. Deneris is a Professor in the Department of Neurosciences and has trained numerous graduate students and postdoctoral fellows. Also, an Advisory Committee of highly-regarded CWRU investigators will provide scientific and career guidance. Using BAC transgenic tools that were made possible by the identification of the Pet-1 cis regulatory region that directs highly reproducible expression of transgenes in developing and adult brain 5-HT neurons, Dr. Deneris developed the ePet-EYFP transgenic mouse line whose 5-HT neurons are genetically marked with enhanced yellow fluorescent protein (EYFP) throughout the lifespan. These mice allow for unprecedented access to 5-HT neurons and targeted gene expression studies specifically in 5HT neurons at any stage of life. The proposed experiments will entail antenatal exposure of pregnant ePet-EYFP mice with the SSRI, fluoxetine. Subsequently, phenotypes of offspring will be examined using behavioral assays and molecular techniques. The specific aims include: 1) Establishing the ePet-EYFP mouse as a valid model of behavioral pathogenesis resulting from antenatal SSRI exposure, and 2) Investigating the molecular effects of antenatal SSRI exposure in ePet-EYFP mice. The combined behavioral and molecular approach in ePet-EYFP mice is unique in basic mental health research. Together, they will test the Principal Investigator's hypothesis that antenatal SSRI exposure will lead to behavioral pathogenesis from perturbations in the regulatory programs that govern 5-HT neuron development.

描述（由申请人提供）：本申请描述了一项为儿科学术生涯的4年培训计划。首席研究员（首席研究员）已在密歇根州/韦恩州立大学医学院儿童医院和波士顿医学院儿童医院的儿科医学和医学毒理学培训完成儿童医院的住院医师培训。现在，他将通过神经科学系与环境健康科学和儿科部门之间的独特部门间合作，分别在Case Western Reserve University（CWRU）的主要研究人员的小学和中学部门之间扩展他的科学技能。部门间合作将为主要研究人员提供指导的研究，职业发展和培训活动，以作为独立研究者的未来职业。该计划将促进管理脊椎动物5-羟色胺（5-HT）系统发展的监管程序的指挥，及其与产前选择性5-羟色胺再摄取抑制剂（SSRI）暴露后的状况。 Evan Deneris博士将指导主要研究者的科学发展，并是大脑5-HT神经递质系统分子遗传学领域的公认领导者。他为理解在整个寿命中起作用的遗传机制做出了基本贡献，以调节5-HT系统功能以及这些机制如何影响5-HT调制行为。他的研究确定了在胚胎调节网络中起作用的PET-1转录因子，以指定小鼠腹侧后脑中的5-HT神经元。 Deneris博士是神经科学系的教授，已经培训了许多研究生和博士后研究员。此外，由备受瞩目的CWRU调查人员组成的咨询委员会将提供科学和职业指导。使用BAC转基因工具通过鉴定PET-1 CIS调节区域使转基因高度可重复地表达在发育和成人脑5-HT神经元中，Deneris博士开发了EPET-EYFP转基因小鼠系列，其5-HT神经元在整个LifeSpan中均具有增强的黄色Fluorescent蛋白（Eyfpp）。这些小鼠允许在生命的任何阶段专门在5HT神经元中专门访问5-HT神经元的前所未有的访问。提出的实验将需要与SSRI氟西汀对怀孕的EPET-EYFP小鼠进行产前暴露。随后，将使用行为测定和分子技术检查后代的表型。具体目的包括：1）将EPET-EYFP小鼠建立为产前SSRI暴露引起的行为发病机制的有效模型，以及2）研究EPET-EYFP小鼠中产前SSRI暴露的分子效应。 EPET-EYFP小鼠中的行为和分子方法在基本的心理健康研究中是独一无二的。他们将共同检验主要研究者的假设，即产前SSRI暴露将导致控制5-HT神经元发展的调节计划中的扰动行为发病机理。