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
基本信息
- 批准号:8851682
- 负责人:
- 金额:$ 13.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdultAffectAllelesAnimal ModelAntidepressive AgentsBase of the BrainBehaviorBehavioralBindingBiologicalBrain regionClinicalCollaborationsComplementComplexDataDepressed moodDevelopmentDevelopment PlansDiseaseEnvironmentEnvironmental Risk FactorEpigenetic ProcessExposure toFetal TissuesFoundationsFutureGene ExpressionGenesGeneticGenetic PolymorphismGenetic TranscriptionGenetic VariationGoalsHealthHeterogeneityHippocampus (Brain)HumanHuman GeneticsIncidenceIndividualIndividual DifferencesInterventionKnowledgeLeadLife StressLinkMeasuresMental DepressionMental disordersMessenger RNAMethodsMethylationModificationMolecularMolecular CloningMood DisordersMusPatternPharmaceutical PreparationsPhenotypePopulationPredispositionPrefrontal CortexPrevalenceProteinsPublic HealthReceptor GeneRelative (related person)ResearchResearch PersonnelResearch Project GrantsResistanceRiskRodent ModelSamplingSerotonin Receptor 5-HT1ASingle Nucleotide PolymorphismSourceStressSumTechniquesTestingTherapeutic InterventionTimeTrainingTranscription Initiation SiteTransgenic MiceTransgenic OrganismsTranslatingTranslational ResearchVariantWorkbasebrain tissuecareercareer developmentdepressed patientdesigneconomic costenvironmental stressorepigenetic regulationepigenetic variationexperiencehuman tissueinsightmouse modelneurogeneticspromoterreceptor expressionrelating to nervous systemskillssuccesstraittranscription factortranslational neurosciencetreatment response
项目摘要
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.
描述(由申请人提供):我的职业目标是领导一个研究正常和病理行为的神经遗传学基础的转化研究小组。为了获得实现这一目标所需的具体训练,我提出了一个项目,研究抑郁症风险的遗传和表观遗传来源的潜在机制,以及它们之间潜在的相互作用。具体来说,我和我未来的实验室将研究5 -羟色胺1a受体基因(HTR1A)的常见遗传和表观遗传变异如何影响HTR1A基因表达,并有助于抑郁风险和抗抑郁药物反应。为了直接转化我们的发现,我们将在死后人体组织和人源化HTR1A小鼠模型中寻求互补技术。我的主要专长是小鼠行为、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,在表观遗传技术、死后人体组织的实验应用以及对精神疾病的更深入理解方面提供必要的新培训。因为我的目标是领导一个研究行为的神经遗传学以及基因表达的改变如何影响疾病状态的实验室,所以我作为一名独立研究人员的成功取决于这些技能。我还建议进一步发展我在转化神经科学方面的训练,以便我
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Zoe Rebecca Donaldson其他文献
Zoe Rebecca Donaldson的其他文献
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The neuromolecular basis of adaptation to bond loss
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9933419 - 财政年份:2018
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$ 13.18万 - 项目类别:
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:
8618070 - 财政年份:2014
- 资助金额:
$ 13.18万 - 项目类别:
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:
9352881 - 财政年份:2014
- 资助金额:
$ 13.18万 - 项目类别:
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