Interrogating genome folding trajectories in health and disease
探究健康和疾病中的基因组折叠轨迹
基本信息
- 批准号:10266185
- 负责人:
- 金额:$ 62.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-30 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAffectAllelesAlzheimer disease screeningAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease therapeuticAnosmiaArchitectureBar CodesBiological AssayCellsChemicalsChromatinChromosomesComplementComplexDNADetectionDevelopmentDevelopmental ProcessDiagnosticDiseaseDown-RegulationEnhancersEnvironmentEnvironmental Risk FactorEpigenetic ProcessEssential GenesEtiologyExhibitsFutureGene ActivationGene ExpressionGene Expression RegulationGene SilencingGenerationsGenesGeneticGenetic Enhancer ElementGenetic TranscriptionGenomeGenomicsHealthHeterochromatinHumanHuman bodyImageIndividualLabelLinkMapsMolecularMusNatural regenerationNerve DegenerationNeuronsNoseNuclearOdorsOlfactory EpitheliumOlfactory PathwaysOlfactory dysfunctionOrganismOutputPharmacologic SubstancePrognosisPropertyReceptor GeneResearchResolutionRoleRouteSpecificityStructureSymptomsSystemTechnologyTranscriptional ActivationTranscriptional RegulationVariantViralbasecell typeexperimental studygenetic manipulationhumanized mousehyposmiain vivoinsightinterdisciplinary approachmolecular imagingmouse modelmutantnerve stem cellneurotoxicitynovelolfactory receptorolfactory sensory neuronsprognosticreceptor expressionsegregationsingle moleculetool
项目摘要
Project Summary
Detection and identification of the astronomical number of volatile chemicals that we perceive as odors
depends upon the monogenic and monoallelic expression of olfactory receptor (OR) genes in olfactory sensory
neurons (OSNs). An intricate network of OSN-specific interchromosomal interactions coordinates the
transcriptional activation of only 1 OR allele out of >2000 OR alleles distributed across 18 different
chromosomes. Genomic interactions between silent OR genes assemble heterochromatic multi-chromosomal
compartments that keep OR genes transcriptionally inactive, whereas genomic interactions between intergenic
OR enhancers result in a multi-chromosomal enhancer hub that activates singular OR transcription. Here, we
propose to combine Dip-C, a variation of single cell HiC, with viral-based cell tagging technologies, towards the
identification of genome folding intermediates across OSN differentiation lineages. This “cradle to crate”
genomic analysis will follow individual OSN progenitors and their barcoded progeny, allowing a complete
cartography of genomic interactions made by every OR allele en route to transcriptional activation. Single
molecule DNA FISH experiments will complement the proposed genomic studies, providing high resolution
insight to the genomic choreography that orchestrates singular OR gene choice during development. Finally,
we seek to explore how the trajectories of OSN genomic folding become altered and eventually disrupted in a
humanized model for Alzheimer’s disease (AD). Olfactory dysfunction, hyposmia, and anosmia constitute well-
established prodromal symptoms of AD, but the molecular etiology of this intriguing connection is not known.
Using a humanized model for AD we discovered that interchromosomal OR compartments dissipate prior to
the onset of neurodegeneration, resulting in strong downregulation of OR transcription. Thus, we propose to
apply our single cell interrogation of genome folding transition in the context of AD and to establish the
baseline of nuclear architecture in human OSNs. Deciphering how OR compartments assemble in health, and
how they become disrupted in disease, may provide the basis for novel prognostic and diagnostic tools for AD,
and molecular assays for in vivo screening of AD therapeutics.
项目摘要
检测和识别天文数字的挥发性化学物质,我们认为是气味
依赖于嗅觉感受器(OR)基因的单基因和单等位基因表达,
神经元(OSNs)。一个复杂的OSN特异性染色体间相互作用网络协调了
>2000个OR等位基因中只有1个OR等位基因的转录激活分布在18个不同的
染色体沉默OR基因之间的基因组相互作用组装异染色质多染色体
保持OR基因转录不活跃的区室,而基因间的基因组相互作用
OR增强子导致激活单一OR转录的多染色体增强子中心。这里我们
我建议将联合收割机Dip-C(单细胞HiC的一种变体)与基于病毒的细胞标记技术相结合,
鉴定跨OSN分化谱系的基因组折叠中间体。这种“从摇篮到板条箱”
基因组分析将跟踪单个OSN祖细胞及其条形码后代,从而允许完整的
每个OR等位基因在转录激活过程中的基因组相互作用的制图。单个
分子DNA FISH实验将补充拟议的基因组研究,提供高分辨率
深入了解基因组编排,编排单一或基因的选择在发展过程中。最后,
我们试图探索OSN基因组折叠的轨迹是如何改变并最终在一个过程中被破坏的。
阿尔茨海默病(AD)的人源化模型。嗅觉障碍,嗅觉减退,嗅觉丧失-
AD的前驱症状,但这种有趣的联系的分子病因学尚不清楚。
使用AD的人源化模型,我们发现染色体间OR区室在AD发生之前消失。
神经变性的发作,导致OR转录的强烈下调。因此,我们建议
应用我们对AD背景下基因组折叠转变的单细胞询问,
人类OSN核结构的基线。解读OR隔室如何在健康状态下组装,
它们在疾病中是如何被破坏的,可能为AD的新的预后和诊断工具提供基础,
以及用于体内筛选AD治疗剂的分子测定。
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 }}
Stavros Lomvardas其他文献
Stavros Lomvardas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 }}
{{ truncateString('Stavros Lomvardas', 18)}}的其他基金
The "olfactosome" as a biomolecular condensate
作为生物分子凝聚物的“嗅觉体”
- 批准号:
10669291 - 财政年份:2022
- 资助金额:
$ 62.27万 - 项目类别:
Olfactory receptor mRNAs as lncRNAs that regulate genomic interactions
嗅觉受体 mRNA 作为调节基因组相互作用的 lncRNA
- 批准号:
10376032 - 财政年份:2020
- 资助金额:
$ 62.27万 - 项目类别:
Principles of zonal olfactory receptor gene expression
带状嗅觉受体基因表达原理
- 批准号:
10350605 - 财政年份:2020
- 资助金额:
$ 62.27万 - 项目类别:
Interrogating genome folding trajectories in health and disease
探究健康和疾病中的基因组折叠轨迹
- 批准号:
10473744 - 财政年份:2020
- 资助金额:
$ 62.27万 - 项目类别:
Olfactory receptor mRNAs as lncRNAs that regulate genomic interactions
嗅觉受体 mRNA 作为调节基因组相互作用的 lncRNA
- 批准号:
10614532 - 财政年份:2020
- 资助金额:
$ 62.27万 - 项目类别:
Principles of zonal olfactory receptor gene expression
带状嗅觉受体基因表达原理
- 批准号:
10570848 - 财政年份:2020
- 资助金额:
$ 62.27万 - 项目类别:
Interrogating genome folding trajectories in health and disease
探究健康和疾病中的基因组折叠轨迹
- 批准号:
10685554 - 财政年份:2020
- 资助金额:
$ 62.27万 - 项目类别:
Deciphering mechanisms of COVID-19 induced anosmia
解读 COVID-19 引起的嗅觉丧失的机制
- 批准号:
10176800 - 财政年份:2020
- 资助金额:
$ 62.27万 - 项目类别:
Non-cell autonomous disruption of genomic interactions as a cause of dementia
基因组相互作用的非细胞自主破坏是痴呆的原因
- 批准号:
10712217 - 财政年份:2020
- 资助金额:
$ 62.27万 - 项目类别:
Interrogating genome folding trajectories in health and disease
探究健康和疾病中的基因组折叠轨迹
- 批准号:
10117398 - 财政年份:2020
- 资助金额:
$ 62.27万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 62.27万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 62.27万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 62.27万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 62.27万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 62.27万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 62.27万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 62.27万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 62.27万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 62.27万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 62.27万 - 项目类别:
Studentship