Behavioral and Molecular Effects of Antenatal SSRI Exposure

产前 SSRI 暴露对行为和分子的影响

• 批准号: 8929383
• 负责人: LAWRENCE S QUANG
• 金额: $ 18.04万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929383
• 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; Genetic study; Genome; Health; 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; differential expression; 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; research study; skills; tool; transcription factor; transgene expression

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）：本申请描述了一个为期4年的培训计划，在儿科学术生涯。主要研究者（主要研究者）已在密歇根儿童医院/韦恩州立大学医学院完成儿科住院医师培训，并在波士顿儿童医院/哈佛医学院完成儿科急诊医学和医学毒理学研究员培训。现在，他将通过凯斯西储大学（CWRU）神经科学系与环境健康科学系和儿科系（主要研究者的主要和次要部门）之间独特的跨部门合作来扩展他的科学技能。跨部门的合作将为主要研究者提供指导研究，职业发展和培训活动，为未来的职业生涯作为一个独立的研究者。该计划将促进控制脊椎动物5-羟色胺（5-HT）系统发育的调节程序的命令，以及产前选择性5-羟色胺再摄取抑制剂（SSRI）暴露后的扰动条件。Evan Deneris博士将指导首席研究员的科学发展，他是大脑5-HT神经递质系统分子遗传学领域公认的领导者。他为理解在整个生命周期中调节5-HT系统功能的遗传机制以及这些机制如何影响5-HT调节行为做出了重要贡献。他的研究已经确定了Pet-1转录因子，该因子在胚胎调节网络中起作用，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，培养了许多研究生和博士后研究员。此外，一个由备受推崇的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顺式调控区（该调控区指导发育中和成年脑5-HT神经元中转基因的高度可重复表达），Deneris博士开发了ePet-EYFP转基因小鼠系，其5-HT神经元在整个生命周期中均以增强型黄色荧光蛋白（EYFP）进行遗传标记。这些小鼠允许前所未有地接触5-HT神经元，并专门针对生命任何阶段的5-HT神经元进行靶向基因表达研究。拟定实验将需要妊娠ePet-EYFP小鼠产前暴露于SSRI氟西汀。随后，将使用行为测定和分子技术检查后代的表型。具体目标包括：1）建立ePet-EYFP小鼠作为产前SSRI暴露导致的行为发病机制的有效模型，和2）研究ePet-EYFP小鼠中产前SSRI暴露的分子效应。ePet-EYFP小鼠的行为和分子结合方法在基础心理健康研究中是独一无二的。他们将共同测试首席研究员的假设，即产前SSRI暴露将导致行为发病机制，从管理5-HT神经元发育的调节程序的扰动。