Evaluating novel architectural proteins as therapeutic targets for cohesin dysfunction
评估新型结构蛋白作为粘连蛋白功能障碍的治疗靶点
基本信息
- 批准号:10593249
- 负责人:
- 金额:$ 24.38万
- 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:2022-09-23 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcuteAddressAffectApplications GrantsArchitectureBinding ProteinsBiological AssayBiologyBruck-de Lange syndromeCALM1 geneCSPG6 geneCandidate Disease GeneCell ProliferationCellsChromatinChromatin LoopChromosomesComplexCongenital Heart DefectsDataDevelopmentDevelopmental Gene Expression RegulationDiseaseDistalEffectivenessEnhancersEnzymesFluorescent in Situ HybridizationFunctional disorderFutureGLI geneGene ExpressionGenesGenetic TranscriptionGenomeGenomicsGoalsHDAC8 geneHeterozygoteHumanHuman Cell LineImageImmunologic Deficiency SyndromesIntellectual functioning disabilityKnowledgeLengthMaintenanceMeasuresMediatingModelingMolecularMutationNeuraxisNuclearOrganPatientsPharmaceutical PreparationsPhenotypePlayProteinsRNA InterferenceReagentRoleSamplingSymptomsSyndromeTechnologyTestingTherapeuticTimeTranslatingValidationWorkbasebody systemcell growthcohesincraniofacialdevelopmental diseasedrug candidateexperimental studygenetic regulatory proteingenomic locusinsightloss of function mutationnovelprogramstherapeutic developmenttherapeutic targettranscriptometranscriptomics
项目摘要
Abstract
Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs
including the central nervous system, inducing a variable neurodevelopmental delay. CdLS is primarily caused
by mutations in regulatory or structural components of the cohesin complex, which are essential Structural
Maintenance of Chromosomes (SMC) protein-containing complexes that interact with chromatin and modulate
genome folding. It is hypothesized that CdLS symptoms are a consequence of transcriptional dysregulation
due to changes in genome architecture upon cohesin disruption. To date, there are no therapies aimed at
correcting cohesin dysfunction or chromatin misfolding directly. These issues are due, in part, to the paucity of
factors known to regulate cohesin-mediated chromatin folding. We performed a high-throughput fluorescent in
situ hybridization (Hi-FISH)-based screen in human cells, which uses Oligopaint probe technology to detect
and measure chromatin interactions in a large number of samples. We targeted ~8,000 human genes, which
represent the “druggable genome” and isolated five candidate genes whose depletion can offset cellular
phenotypes associated with cohesin dysfunction. The goal of this proposal is to characterize the role of these
novel ‘anti-cohesin factors’ in nuclear architecture and cohesin function and test the ability of their inhibition to
correct gene misexpression in CdLS models. Through understanding the molecular factors involved in cohesin
biology and chromatin folding, we can begin to consider targeted approaches to CdLS therapeutic
development.
摘要
科尔内利亚德兰格综合征(CdLS)是一种罕见的发育障碍,影响了众多的器官
包括中枢神经系统,引起可变的神经发育延迟。CDLS主要是由
通过在粘附素复合物的调节或结构组分中的突变,这是必不可少的
维持与染色质相互作用并调节的含有染色体(SMC)蛋白的复合物
基因组折叠据推测,CdLS症状是转录失调的结果
这是由于内聚蛋白破坏后基因组结构的变化。到目前为止,还没有针对
直接纠正粘连蛋白功能障碍或染色质错误折叠。这些问题的部分原因是,
已知调节粘着蛋白介导的染色质折叠的因子。我们进行了高通量的荧光检测,
在人类细胞中进行基于原位杂交(Hi-FISH)的筛选,使用Oligopaint探针技术检测
并测量大量样本中的染色质相互作用。我们瞄准了约8,000个人类基因,
代表“可药物化的基因组”,并分离出五个候选基因,
与粘附素功能障碍相关的表型。本提案的目的是描述这些机构的作用,
新的“抗粘连蛋白因子”在核结构和粘连蛋白功能中的作用,并测试它们抑制
在CdLS模型中纠正基因错误表达。通过了解参与粘附素的分子因素
生物学和染色质折叠,我们可以开始考虑有针对性的方法来CdLS治疗
发展
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)
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Eric F. Joyce其他文献
B cell stimulation changes the structure and higher-order organization of the inactive X chromosome
B 细胞刺激改变了非活性 X 染色体的结构和高阶组织。
- DOI:
10.1016/j.celrep.2025.115351 - 发表时间:
2025-03-25 - 期刊:
- 影响因子:6.900
- 作者:
Isabel Sierra;Natalie E. Toothacre;Robin H. van der Weide;Claudia D. Lovell;Son C. Nguyen;R. Jordan Barnett;Ashley L. Cook;Han-Seul Ryu;Sarah Pyfrom;Harrison Wang;Daniel Beiting;Jennifer E. Philips-Cremins;Eric F. Joyce;Montserrat C. Anguera - 通讯作者:
Montserrat C. Anguera
Nuclear speckles regulate functional programs in cancer
核斑调节癌症中的功能程序
- DOI:
10.1038/s41556-024-01570-0 - 发表时间:
2025-01-02 - 期刊:
- 影响因子:19.100
- 作者:
Katherine A. Alexander;Ruofan Yu;Nicolas Skuli;Nathan J. Coffey;Son Nguyen;Christine L. Faunce;Hua Huang;Ian P. Dardani;Austin L. Good;Joan Lim;Catherine Y. Li;Nicholas Biddle;Eric F. Joyce;Arjun Raj;Daniel Lee;Brian Keith;M. Celeste Simon;Shelley L. Berger - 通讯作者:
Shelley L. Berger
Multiple allelic configurations govern long-range emShh/em enhancer-promoter communication in the embryonic forebrain
多个等位基因配置控制胚胎前脑中的远程EMSHH/EM Enhancer启动器通信
- DOI:
10.1016/j.molcel.2024.10.042 - 发表时间:
2024-12-19 - 期刊:
- 影响因子:16.600
- 作者:
Jailynn Harke;Jeewon R. Lee;Son C. Nguyen;Arian Arab;Staci M. Rakowiecki;Siewert Hugelier;Christina Paliou;Antonella Rauseo;Rebecca Yunker;Kellen Xu;Yao Yao;Melike Lakadamyali;Guillaume Andrey;Douglas J. Epstein;Eric F. Joyce - 通讯作者:
Eric F. Joyce
Eric F. Joyce的其他文献
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{{ truncateString('Eric F. Joyce', 18)}}的其他基金
Evaluating novel architectural proteins as therapeutic targets for cohesin dysfunction
评估新型结构蛋白作为粘连蛋白功能障碍的治疗靶点
- 批准号:
10709896 - 财政年份:2022
- 资助金额:
$ 24.38万 - 项目类别:
Regulation of chromatin folding in space and time
染色质折叠在空间和时间上的调节
- 批准号:
10622801 - 财政年份:2018
- 资助金额:
$ 24.38万 - 项目类别:
Regulation of chromatin folding in space and time
染色质折叠在空间和时间上的调节
- 批准号:
10429968 - 财政年份:2018
- 资助金额:
$ 24.38万 - 项目类别:
Regulation of chromatin folding in space and time
染色质折叠在空间和时间上的调节
- 批准号:
10187589 - 财政年份:2018
- 资助金额:
$ 24.38万 - 项目类别:
Regulation of chromatin folding in space and time
染色质折叠在空间和时间上的调节
- 批准号:
10173179 - 财政年份:2018
- 资助金额:
$ 24.38万 - 项目类别:
Exploring the mechanism and function of somatic homolog pairing
探索体细胞同源配对的机制和功能
- 批准号:
8548919 - 财政年份:2011
- 资助金额:
$ 24.38万 - 项目类别:
Exploring the mechanism and function of somatic homolog pairing
探索体细胞同源配对的机制和功能
- 批准号:
8341015 - 财政年份:2011
- 资助金额:
$ 24.38万 - 项目类别:
Exploring the mechanism and function of somatic homolog pairing
探索体细胞同源配对的机制和功能
- 批准号:
8060338 - 财政年份:2011
- 资助金额:
$ 24.38万 - 项目类别:
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