Variation in serotonin 1a receptor expression as a source of depression risk

血清素 1a 受体表达的变化是抑郁症风险的一个来源

• 批准号: 8851682
• 负责人: Zoe Rebecca Donaldson
• 金额: $ 13.18万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851682
• 关键词: Adult; Affect; Alleles; Animal Model; Antidepressive Agents; Base of the Brain; Behavior; Behavioral; Binding; Biological; Brain region; Clinical; Collaborations; Complement; Complex; Data; Depressed mood; Development; Development Plans; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Exposure to; Fetal Tissues; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Goals; Health; Heterogeneity; Hippocampus (Brain); Human; Human Genetics; Incidence; Individual; Individual Differences; Intervention; Knowledge; Lead; Life Stress; Link; Measures; Mental Depression; Mental disorders; Messenger RNA; Methods; Methylation; Modification; Molecular; Molecular Cloning; Mood Disorders; Mus; Pattern; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Prefrontal Cortex; Prevalence; Proteins; Public Health; Receptor Gene; Relative (related person); Research; Research Personnel; Research Project Grants; Resistance; Risk; Rodent Model; Sampling; Serotonin Receptor 5-HT1A; Single Nucleotide Polymorphism; Source; Stress; Sum; Techniques; Testing; Therapeutic Intervention; Time; Training; Transcription Initiation Site; Transgenic Mice; Transgenic Organisms; Translating; Translational Research; Variant; Work; base; brain tissue; career; career development; depressed patient; design; economic cost; environmental stressor; epigenetic regulation; epigenetic variation; experience; human tissue; insight; mouse model; neurogenetics; promoter; receptor expression; relating to nervous system; skills; success; trait; transcription factor; translational neuroscience; treatment response

DESCRIPTION (provided by applicant): My career goal is to lead a translational research group that investigates the neurogenetic basis of both normal and pathological behavior. To acquire the specific training I will need to achieve this, I propose a project that examines the mechanisms underlying genetic and epigenetic sources of depression risk, as well as their potential interaction. Specifically, I, and my future lab, will investigate how common genetic and epigenetic variation in the serotonin 1a receptor gene (HTR1A) impacts HTR1A gene expression and contributes to both depression risk and anti-depressant drug responsiveness. To directly translate our findings, we will pursue complimentary techniques in post-mortem human tissue and a humanized HTR1A mouse model. My primary expertise is in mouse behavior, molecular cloning, and transgenic techniques; my career development plan expands on these methods, providing essential new training in epigenetic techniques, experimental use of post-mortem human tissue, and a deeper understanding of psychiatric disorders. Since it is my goal to lead a lab that studies the neurogenetics of behavior and how alterations in gene expression contribute to disease states, my success as an independent researcher depends on these skills. I also propose to further develop my training in translational neuroscience so that I may expand my clinical collaborations. Research Project Identifying the biological mechanisms underlying both heritable and non-heritable factors that impact depression risk and treatment response is of the utmost importance for designing better therapies and preventative interventions. While substantial evidence from both humans and rodent models has linked variation in serotonin 1a receptor (5-HT1A) levels with depression-related traits, the biological mechanisms underlying differences in receptor expression are not well understood. Preliminary evidence suggests that both rs6295, a common single nucleotide polymorphism (SNP) located upstream of the HTR1A gene, and methylation of the HTR1A promoter impact 5-HT1A levels. However, the direct contribution and potential interaction of these putative sources of variation in expression have not been demonstrated. Thus, we here propose to investigate the hypothesis that both epigenetic and genetic variation affect susceptibility to depression and resistance to antidepressants by modulating 5-HT1A levels. To test this, we will first examine the relationship between rs6295 and levels of HTR1A mRNA in post-mortem human brain tissue. Then we will use a humanized mouse model to determine the direct contribution of rs6295 to 5-HT1A levels, depression- related behavior, and antidepressant responsiveness. Using these mice, we will also examine the effects of stress exposure on HTR1A transcription, methylation of the human HTR1A promoter, and behavior. Finally, we will combine these lines of questioning to ask whether rs6295 interacts with stress exposure at a molecular (i.e., epigenetic) and/or behavioral level.

职位描述(申请人提供)：我的职业目标是领导一个翻译研究小组，研究正常和病态行为的神经遗传学基础。为了获得实现这一目标所需的具体培训，我提出了一个项目，研究抑郁症风险的遗传来源和表观遗传来源的潜在机制，以及它们之间的潜在相互作用。具体地说，我和我未来的实验室将调查5-羟色胺1a受体基因(HTR1A)常见的遗传和表观遗传变异如何影响HTR1A基因的表达，并对抑郁风险和抗抑郁药物反应性做出贡献。为了直接翻译我们的发现，我们将在死后的人类组织和人源化的HTR1a小鼠模型上进行补充技术。我的主要专长是老鼠行为、分子克隆和转基因技术；我的职业发展计划扩展了这些方法，提供了必要的新培训，包括表观遗传技术、死后人体组织的实验使用以及对精神疾病的更深入理解。由于我的目标是领导一个实验室，研究行为的神经遗传学以及基因表达的变化如何导致疾病状态，我作为一名独立研究人员的成功依赖于这些技能。我还建议进一步发展我在翻译神经科学方面的培训，以便我 可能会扩大我的临床合作。研究项目确定影响抑郁症风险和治疗反应的遗传和非遗传因素背后的生物学机制，对于设计更好的治疗方法和预防性干预措施至关重要。虽然来自人类和啮齿动物模型的大量证据已将5-羟色胺1a受体(5-HT1A)水平的变化与抑郁症相关特征联系在一起，但受体表达差异背后的生物学机制尚不清楚。初步证据表明，位于HTR1A基因上游的常见单核苷酸多态(SNP)rs6295和HTR1A启动子的甲基化都会影响5-HT1A水平。然而，这些假定的表达变异来源的直接贡献和潜在的相互作用还没有被证明。因此，我们建议研究这一假说，即表观遗传和遗传变异都通过调节5-HT1a水平来影响抑郁症的易感性和抗抑郁剂的耐药性。为了验证这一点，我们将首先检查rs6295与死后人脑组织中HTR1a mRNA水平的关系。然后，我们将使用人源化的小鼠模型来确定rs6295对5-HT1a水平、抑郁相关行为和抗抑郁药物反应性的直接贡献。利用这些小鼠，我们还将检查应激暴露对HTR1A转录、人类HTR1A启动子甲基化和行为的影响。最后，我们将结合这些问题来询问rs6295是否在分子(即表观遗传)和/或行为水平上与压力暴露相互作用。