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: 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
• 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

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 年的儿科学术职业培训计划。首席研究员（Principal Investigator）已在密歇根儿童医院/韦恩州立大学医学院完成了儿科住院医师培训，并在波士顿儿童医院/哈佛医学院完成了儿科急诊医学和医学毒理学方面的进修培训。他现在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（分别是首席研究员的主要和次要部门）之间独特的跨部门合作来扩展他的科学技能。跨部门合作将为首席研究员提供指导性研究、职业发展和培训活动，以帮助其作为一名独立研究者未来的职业生涯。该计划将促进对管理脊椎动物血清素（5-HT）系统发育及其在产前选择性血清素再摄取抑制剂（SSRI）暴露扰动后的状况的监管计划的指挥。 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 调节行为做出了基础性贡献。他的研究发现了 Pet-1 转录因子，该因子在胚胎调节网络中发挥作用，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，培养了众多研究生和博士后。此外，由备受推崇的 CWRU 研究人员组成的咨询委员会将提供科学和职业指导。 Deneris 博士使用 BAC 转基因工具开发了 ePet-EYFP 转基因小鼠系，该工具是通过识别 Pet-1 顺式调节区而成为可能的，该调节区指导发育中和成年大脑 5-HT 神经元中转基因的高度可重复表达。 HT 神经元在整个生命周期中都带有增强型黄色荧光蛋白 (EYFP) 的基因标记。这些小鼠可以前所未有地接触 5-HT 神经元，并进行靶向基因表达研究，特别是在生命的任何阶段的 5HT 神经元中。拟议的实验将需要使怀孕的 ePet-EYFP 小鼠在产前接触 SSRI（氟西汀）。随后，将使用行为分析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 暴露引起的行为发病机制的有效模型，2) 研究产前 SSRI 暴露对 ePet-EYFP 小鼠的分子影响。 ePet-EYFP 小鼠的行为和分子相结合的方法在基础心理健康研究中是独一无二的。他们将共同检验首席研究员的假设，即产前接触 SSRI 会因控制 5-HT 神经元发育的调节程序扰动而导致行为发病机制。