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

描述（由申请人提供）：我的职业目标是领导一个翻译研究小组，调查正常和病理行为的神经遗传学基础。为了获得实现这一目标所需的特定培训，我提出了一个项目，研究抑郁风险的遗传和表观遗传来源的机制，以及它们之间的潜在相互作用。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（HTR 1A）中常见的遗传和表观遗传变异如何影响HTR 1A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HTR 1A小鼠模型中寻求补充技术。 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，提供表观遗传技术，死后人体组织的实验性使用的新培训，以及对精神疾病的更深入了解。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培训， 可以扩大我的临床合作确定影响抑郁症风险和治疗反应的遗传和非遗传因素的生物学机制对于设计更好的治疗和预防干预措施至关重要。虽然来自人类和啮齿动物模型的大量证据将5-羟色胺1a受体（5-HT 1A）水平的变化与抑郁症相关性状联系起来，但受体表达差异的生物学机制尚未得到很好的理解。初步证据表明，位于HTR 1A基因上游的常见单核苷酸多态性（SNP）rs6295和HTR 1A启动子的甲基化都会影响5-HT 1A水平。然而，这些假定的表达变异来源的直接贡献和潜在相互作用尚未得到证实。因此，我们在这里建议调查的假设，即表观遗传和遗传变异影响抑郁症的易感性和抗抑郁药的抗调制5-HT 1A水平。为了验证这一点，我们将首先研究rs6295和死后人脑组织中HTR 1A mRNA水平之间的关系。然后，我们将使用人源化小鼠模型来确定rs6295对5-HT 1A水平、抑郁相关行为和抗抑郁剂反应性的直接贡献。使用这些小鼠，我们还将研究应激暴露对HTR 1A转录，人类HTR 1A启动子甲基化和行为的影响。最后，我们将联合收割机结合这些问题来询问rs6295是否在分子水平上与应激暴露相互作用（即，表观遗传）和/或行为水平。

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.