Regulatory Elements Controlling Anxiety States

控制焦虑状态的监管要素

• 批准号: 10371661
• 负责人: Dimitri Traenkner
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371661
• 关键词: Ablation; Address; Adult; Affect; American; Animal Model; Anxiety; Anxiety Disorders; Behavior; Binding; Binding Sites; Brain; Candidate Disease Gene; Cause of Death; Cells; ChIP-seq; Complex; Compulsive Behavior; Data; Detection; Development; Diagnosis; Embryo; Embryonic Development; Equilibrium; Female; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genes; Gonadal Steroid Hormones; Grooming; Hormones; Human; Hydrocortisone; In Situ; Life; Ligation; Light; Link; Mammals; Maps; Mental Health; Mental disorders; Methodology; Methods; Microglia; Modeling; Molecular; Moods; Mus; Pathological anxiety; Pathology; Persons; Phenotype; Physiological; Play; Predisposition; Prevalence; Prevention; Proteins; Public Health; Regulator Genes; Regulatory Element; Reporting; Reproduction; Research; Risk; Risk Factors; Risk-Taking; Role; Sex Bias; Shapes; Suicide; Symptoms; Targeted Research; Testing; United States; Universities; Utah; Woman; anxiety states; anxiety symptoms; anxiety treatment; base; behavioral phenotyping; biological adaptation to stress; cell type; combat; disorder risk; experience; female sex hormone; gene function; genetic risk assessment; genetic risk factor; genome wide association study; hormonal signals; improved; in situ sequencing; mouse model; offspring; promoter; reproductive; resilience; risk variant; sex; stem cells; success; transcription factor; transcriptome sequencing; treatment of anxiety disorders

PROJECT SUMMARY About one in three U.S. Americans experiences disabling anxiety at some point in life, and about 60% of those affected are women. Available anxiety treatments only temporarily improve mood with variable success, underscoring the need for new paths in the combat against anxiety disorders. Gene regulatory mechanisms are emerging as major drivers of mental health risks. Understanding how gene regulatory mechanisms influence anxiety phenotypes is essential for the development of more precise assessment of genetic risk, diagnosis, and targeted treatments of anxiety disorders. We recently showed that disruption of the transcription factor HoxB8 produces severe anxiety symptoms in mice likely due to the dysfunction in a subset of microglia and that the pathology scales with levels of female sex hormones. Since Hox transcription factors have highly conserved functions across all vertebrate species, our findings in mice likely apply to some extend to humans. In fact, our preliminary study revealed that in humans HoxB8-binding sites are disproportionally often in contact with promotors of anxiety-risk genes, but it is unclear how these genes are linked to microglia. Here, we test the hypothesis that HoxB8-activity is associated with genetic risk factors for anxiety disorders and that these risk factors act via microglia. Based on the strong sex-linked and hormone-controlled phenotype in mice, our expanded hypothesis is that HoxB8 enables microglia to tune brain circuits for cautious versus risk-taking behaviors during the reproductive cycle. Two aims proposed here address our immediate hypothesis. Aim 1 defines HoxB8-dependent gene regulatory elements and genes at several developmental stages and Aim 2 explores the expression of HoxB8-linked anxiety-risk genes in microglia of mice. Identified regulatory elements and associated genes will be aligned with genome-wide association study (GWAS) data to evaluate their role in anxiety disorders. The expression tests will further substantiate the role of microglia in HoxB8-controlled anxiety, shed first light on the underlying molecular mechanisms, and set stage for direct functional studies in the future.

项目摘要 大约三分之一的美国美国人在生活的某个时候经历了焦虑，其中约60％ 受影响的是女性。可用的焦虑治疗仅通过可变成功而暂时改善情绪， 强调了针对焦虑症的战斗中对新道路的需求。基因调节机制是 成为心理健康风险的主要驱动因素。了解基因调节机制如何影响 焦虑表型对于更精确评估遗传风险，诊断和 焦虑症的有针对性治疗。我们最近表明转录因子HOXB8的破坏 小鼠的小鼠产生严重的焦虑症状，可能是由于小胶质细胞的功能障碍而引起的，并且 病理学与女性性激素水平相比。由于HOX转录因子具有高度保守的 在所有脊椎动物物种中的功能，我们在小鼠中的发现可能适用于人类。实际上，我们的 初步研究表明，在人类中，hoxb8结合位点经常与 焦虑风险基因的启动子，但尚不清楚这些基因如何与小胶质细胞相关。在这里，我们测试 HOXB8活性与焦虑症的遗传危险因素有关的假说，这些风险 因素通过小胶质细胞起作用。基于小鼠中强烈的性别连接和激素控制的表型，我们 扩展的假设是HOXB8使小胶质细胞能够调整脑电路的谨慎与冒险 生殖周期中的行为。这里提出的两个目的解决了我们的直接假设。目标1 在几个发育阶段定义HOXB8依赖性基因调节元件和基因，目标2 探索小鼠小胶质细胞中HOXB8连锁焦虑风险基因的表达。确定的监管要素 并将相关的基因与全基因组关联研究（GWAS）数据一致，以评估其在 焦虑症。表达测试将进一步证实小胶质细胞在HOXB8控制的焦虑中的作用， 首先阐明了基本的分子机制，并为将来的直接功能研究设定了阶段。