Regulatory Elements Controlling Anxiety States

控制焦虑状态的监管要素

基本信息

批准号：
10678822
负责人：
Dimitri Traenkner
金额：
$ 19.25万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678822
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 Chromosome Mapping 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 Link Mammals Mental Health Mental disorders Methodology Methods Microglia Modeling Molecular Moods Mus Neuroglia 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 behavioral phenotyping biological adaptation to stress cell type combat disorder risk experience female sex hormone gene conservation 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

项目摘要

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.

项目概要大约三分之一的美国人在人生的某个阶段经历过失能性焦虑，其中大约 60% 受影响的是妇女。现有的焦虑治疗只能暂时改善情绪，但效果参差不齐，强调对抗焦虑症需要新的途径。基因调控机制是正在成为心理健康风险的主要驱动因素。了解基因调控机制如何影响焦虑表型对于更精确地评估遗传风险、诊断和治疗至关重要焦虑症的针对性治疗。我们最近发现转录因子 HoxB8 的破坏小鼠产生严重的焦虑症状可能是由于小胶质细胞亚群的功能障碍以及病理学与女性性激素水平有关。由于Hox转录因子高度保守由于该功能适用于所有脊椎动物物种，因此我们在小鼠身上的发现可能在某种程度上适用于人类。事实上，我们的初步研究表明，在人类中，HoxB8 结合位点不成比例地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，我们测试假设 HoxB8 活性与焦虑症的遗传风险因素有关，并且这些风险因子通过小胶质细胞起作用。基于小鼠中强烈的性相关和激素控制的表型，我们的扩展的假设是 HoxB8 使小胶质细胞能够调整大脑回路，以谨慎行事和冒险生殖周期中的行为。这里提出的两个目标解决了我们直接的假设。目标1 定义了几个发育阶段的 HoxB8 依赖性基因调控元件和基因以及目标 2 探讨 HoxB8 相关焦虑风险基因在小鼠小胶质细胞中的表达。已确定的监管要素相关基因将与全基因组关联研究（GWAS）数据进行比对，以评估它们在焦虑症。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，首次揭示了潜在的分子机制，并为未来的直接功能研究奠定了基础。