Promoting Resilience to Early Life Stress through Epigenetic Editing
通过表观遗传编辑提高对早期生活压力的抵抗力
基本信息
- 批准号:10536990
- 负责人:
- 金额:$ 3.08万
- 依托单位:
- 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:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcuteAdolescentAdoptedAdultAnimal ExperimentationAnxietyAnxiety DisordersArchitectureAutomobile DrivingAwardBehaviorBehavioralBioinformaticsBrainCell NucleusCellsChild Abuse and NeglectChildhoodChromatinChromatin StructureClinical ResearchClustered Regularly Interspaced Short Palindromic RepeatsComplexComputer AnalysisDNADataData AnalysesDevelopmentEnhancersEpigenetic ProcessFemaleFoundationsFutureGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGenomeGenomicsGlutamatesHumanHypersensitivityIn VitroLabelLifeLinkLongevityMeasuresMediatingMental DepressionMental disordersMolecularMolecular ConformationMood DisordersMusNeurobiologyNeuronsNuclear EnvelopeNucleus AccumbensParentsPathway interactionsPovertyPredispositionResearchRewardsRiskRisk FactorsSexual abuseSignal TransductionStimulusStressSumSystemTestingTranscriptional RegulationTransgenic MiceTraumaWorkXCL1 geneabuse neglectbasebehavioral responsebiological adaptation to stressbrain cellcareercomparativedisorder riskearly experienceearly life stressemotional abuseepigenomeepigenome editingexperienceexperimental studygenomic locushistone modificationin vivoinsightlifetime riskmalemouse modelneuropsychiatryphysical abusepreventrelating to nervous systemresilienceresponsereward circuitrysexstressorthree dimensional structuretoolwhole genome
项目摘要
PROJECT SUMMARY / ABSTRACT
Early life stress (ELS) is one of the strongest predictors for development of mood and anxiety disorders.
ELS can include trauma (neglect, and/or physical, sexual, and/or emotional abuse) or other negative childhood
experiences. However, the increased risk for depression following ELS is not well understood. Previous work in
a mouse model of stress across the lifespan has shown unique gene expression patterns after ELS and adult
stress in the nucleus accumbens (NAc), a key region of the reward pathway implicated in stress response. The
three-dimensional structure of chromatin is a key factor in determining how genes are regulated and
expressed, with more open and accessible chromatin being permissive for gene expression and more closed
chromatin repressing expression. We hypothesize that ELS changes chromatin accessibility within
stress-responsive neuronal cells in the NAc such that the chromatin adopts a comparatively open
conformation, making transcription more reactive to future stimuli. In Aim 1, I will determine how chromatin
architecture is altered specifically within ELS-activated neurons using a double-transgenic mouse to label and
capture both activated and non-activated neurons, then perform ATAC-sequencing and computational analyses
to determine chromatin accessibility across the entire genome. I will examine how ELS alters chromatin
structure in activated and non-activated cells in juvenile and adult mice of both sexes. In Aim 2, I will test the
functional impact of chromatin state on transcriptional and behavioral susceptibility to adulthood stressors.
First, I will apply CRISPR-dCas9-based epigenome editing tools to close chromatin at target genomic
enhancer regions already identified in preliminary data to prevent hypersensitivity to activation in vitro. Then, I
will use this tool in vivo to test the hypothesis that closing aberrantly open chromatin can reverse the impact of
ELS and promote transcriptional and behavioral resilience. Together, this research will generate fundamental
insights into how stress during key periods of development increases sensitivity to future stress at a molecular
level in the brain.This project contributes to our understanding of the epigenetic mechanisms driving
heightened risk of mood disorders following ELS.
项目总结/摘要
早期生活压力(ELS)是情绪和焦虑障碍发展的最强预测因素之一。
ELS可包括创伤(忽视和/或身体、性和/或情感虐待)或其他负面童年
经验然而,ELS后抑郁症的风险增加还没有得到很好的理解。以前的工作
一个小鼠模型的压力在整个生命周期显示出独特的基因表达模式后,ELS和成人
神经核(NAc)中的压力,这是与压力反应有关的奖励途径的关键区域。的
染色质的三维结构是决定基因如何调节的关键因素,
表达,其中更开放和可接近的染色质允许基因表达,而更封闭的染色质允许基因表达。
染色质抑制表达。我们假设ELS改变了细胞内的染色质可及性,
在NAc中的应激反应神经元细胞,使得染色质采用相对开放的
构象,使转录对未来的刺激更具反应性。在目标1中,我将确定染色质如何
使用双转基因小鼠标记并在ELS激活的神经元内特异性改变结构,
捕获激活和未激活的神经元,然后进行ATAC测序和计算分析
来确定整个基因组的染色质可及性。我将研究ELS如何改变染色质
在两种性别的幼年和成年小鼠的活化和非活化细胞中的结构。在目标2中,我将测试
染色质状态对转录和行为对成年期压力的易感性的功能影响。
首先,我将应用基于CRISPR-dCas 9的表观基因组编辑工具,
增强子区域已经在初步数据中确定,以防止体外活化的超敏反应。那我
将在体内使用这种工具来测试关闭异常开放的染色质可以逆转
ELS和促进转录和行为弹性。总之,这项研究将产生基本的
深入了解关键发育时期的压力如何增加分子水平对未来压力的敏感性
这个项目有助于我们理解表观遗传机制,
ELS后情绪障碍的风险增加。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Rebekah Rashford其他文献
Rebekah Rashford的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 3.08万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 3.08万 - 项目类别:
Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 3.08万 - 项目类别:
Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 3.08万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 3.08万 - 项目类别:
Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 3.08万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 3.08万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 3.08万 - 项目类别:
Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 3.08万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
- 批准号:
2244994 - 财政年份:2023
- 资助金额:
$ 3.08万 - 项目类别:
Standard Grant