Genetic Models of Serotonin Transporter Regulation Linked to Mental Disorders

与精神疾病相关的血清素转运蛋白调节的遗传模型

• 批准号: 8585969
• 负责人: SAMMANDA RAMAMOORTHY
• 金额: $ 7.25万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585969
• 关键词: Genetic; Models; Serotonin; Transporter; Regulation

DESCRIPTION (provided by applicant): Altered serotonergic transmission and presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) expression have long been associated with psychiatric disorders including depression, suicide, autism, OCD, impulsive violence. Indeed, the drugs that block SERT such as tricyclic antidepressants and SSRIs are successfully used for the treatment of mental disorders. Studies from PI's group, collaborators and colleagues have identified signaling mechanisms of SERT regulation by kinases/phosphatases. Remarkably, the association of human SERT coding variants Gly56Ala, Ile425Val mutation with OCD, autism and other psychiatric disorders, and the discovery that these mutations alter PKG/p38 MAPK regulation of SERT activity suggest that this form of regulation is important in the normal physiology of SERT and dysregulation of SERT may influence risk for disorders attributed to compromised 5-HT signaling. Currently no transgenic animal models are available to test whether altered SERT phosphorylation is causative for altered behavior found in autism, OCD and other psychiatric disorders. In this R21 proposal, recognizing the risk versus reward mission, we propose to test the hypothesis that transgenic mouse models mimicking constitutive SERT PKG-phosphorylation show gain of 5-HT transport phenotype with loss of PKG-mediated upregulation and phosphorylation rescuing behavioral phenotypes that parallel Ile425Val mutant identified in OCD and Asperger syndrome. In Specific Aim 1, we propose to construct targeting vectors carrying Thr276Asp mutation that mimic PKG-phosphorylation and Ile425Val mutation associated with OCD and Asperger syndrome by inserting the mutations into mouse SERT genomic sequences to generate SERT transgenic SERT mice. Specific Aim 2 will validate SERT regulation and phosphorylation in Thr276Asp and Ile425Val SERT mice, and elucidate important 5-HT related behavioral phenotypes rescued in the knock-in mice. However, future studies that are beyond the scope of this proposal, will utilize Thr276Asp and/or Ile425Val knock-in SERT mice to analyze neurochemical, behavioral and gene expression profiles, and to measure responses to acute and chronic in vivo SSRI administrations and other therapeutic agents. Thus, generation of these unique mouse models provide innovative tools for exploring the kinase mediated SERT regulatory pathways that are set points in disrupting normal SERT function found in disease-linked human SERT variants. In addition, these SERT transgenic mice will aid future studies exploring serotonin-related gene regulatory network that may be linked to mental disorders and in the development of effective pharmacological agents for the treatment of mental disorders. PUBLIC HEALTH RELEVANCE: The association of human SERT coding variants Gly56Ala, Ile425Val mutation with OCD, autism and other psychiatric disorders, and the discovery that these mutants alter PKG/p38 MAPK regulation of SERT activity suggest that this form of regulation is important in the normal physiology of SERT. The proposed research to generate a knock-in mouse model will enable to identify the neuronal network linked to mental disorders and aid in the development of effective pharmacological agents for the treatment of mental disorders and other disease states resulting from aberrant monoamine transmission.

描述（由申请人提供）：详尽的5-羟色胺传播和突触前5-羟色胺（5-羟色胺，5-HT）转运蛋白（SERT）表达长期以来一直与精神疾病有关，包括抑郁症，自杀，自闭症，自闭症，OCD，OCD，冲动性暴力。实际上，阻止SERT（例如三环抗抑郁药和SSRI）的药物成功地用于治疗精神疾病。 PI小组，合作者和同事的研究确定了激酶/磷酸酶的SERT调节信号传导机制。值得注意的是，人类SERT编码变体的关联Gly56Ala，Ile425Val突变与强迫症，自闭症和其他精神疾病的发现，并且发现这些突变会改变PKG/p38 MAPK调节Sert活性的调节，这表明这种调节形式对Sert和Sert的正常物理学的影响可能对Sert和dysemed signers的正常物理学有影响，这可能会影响5-疾病的影响。目前，尚无转基因动物模型可用于测试SERT磷酸化改变是否是自闭症，强迫症和其他精神疾病中发现的改变行为的原因。 In this R21 proposal, recognizing the risk versus reward mission, we propose to test the hypothesis that transgenic mouse models mimicking constitutive SERT PKG-phosphorylation show gain of 5-HT transport phenotype with loss of PKG-mediated upregulation and phosphorylation rescuing behavioral phenotypes that parallel Ile425Val mutant identified in OCD and Asperger syndrome.在特定的目标1中，我们建议构建携带Thr276asp突变的靶向向量，以模拟与OCD和Asperger综合征相关的PKG-磷酸化和ILE425VAL突变，并通过将突变插入小鼠SERT基因组序列中以产生SERT SERT TRANSTENIC SERT MIET。具体目标2将验证THR276ASP和ILE425VAL SERT小鼠中的SERT调节和磷酸化，并阐明在敲入小鼠中救出的重要5-HT相关行为表型。但是，未来的研究超出了该提案的范围，将利用THR276ASP和/或ILE425VAL敲入SERT小鼠分析神经化学，行为和基因表达谱，并衡量对急性和慢性体内体内SSRI管理和其他治疗疗法的反应。因此，这些独特的小鼠模型的生成提供了创新的工具，用于探索激酶介导的SERT调节途径，这些途径是破坏疾病连接的人类Sert变体中正常SERT功能的设定点。此外，这些SERT转基因小鼠将有助于未来的研究，探索可能与精神障碍以及开发有效的药理学剂来治疗精神障碍的基因调节网络。 公共卫生相关性：人类SERT编码变体的关联Gly56ALA，ILE425VAL突变与强迫症，自闭症和其他精神疾病，并且发现这些突变体会改变PKG/p38 MAPK的SERT活性调节，这表明这种调节形式在Sert的正常生理学中很重要。提出的旨在产生敲门小鼠模型的研究将使与精神障碍相关的神经元网络，并有助于开发有效的药理学剂，以治疗异常单胺传播引起的精神障碍和其他疾病状态。