Targeted Gene Regulation Using Engineered Synthetic Transcriptional Regulators
Targeted Gene Regulation Using Engineered Synthetic Transcriptional Regulators
批准号:
10729851
负责人:
Colin Stuart Swenson
金额:
$6.95万
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
项目状态:
已结题
起止时间:
2022-09-01 至 2024-08-31
关键词:
AffectAffinityAntibodiesApoptosisAutoimmunityBindingBinding ProteinsBinding SitesBiological ProcessBiological ProductsBreathingCellsCharacteristicsChimeric ProteinsChromatin StructureDNADNA BindingDNA Binding DomainDNA-Protein InteractionDiabetes MellitusDimerizationDiseaseEngineeringEnhancersFunctional disorderFutureGene ExpressionGene Expression RegulationGene SilencingGenerationsGenesGenetic TranscriptionGenomeGenomic DNAGenomicsHomeostasisInvestigationLeadLibrariesLigationLinkMalignant NeoplasmsMediatingNatureOncogenicPermeabilityPhenotypePreparationProcessPromoter RegionsPropertyProteinsProto-Oncogene Proteins c-mycRNAResearchRoleRouteSiteSolubilitySpecificityStructureTechnologyTestingTherapeuticantagonistclinically relevantcofactordesigndimerdrug discoveryeffective therapyempowermentgene repressionimprovedinnovationlead optimizationmimeticsmonomernervous system disordernovel strategiespharmacologicprogramspromoterrational designrecruitsmall moleculesuccesssynthetic constructtargeted treatmenttherapeutically effectivetooltranscription factor
中文摘要
项目摘要
转录因子是通过直接相互作用调节基因表达的关键功能蛋白
基因组 DNA 的特定序列,从而激活或抑制转录。这个高度保守的
该过程控制许多核心生物功能,包括细胞稳态、分化和凋亡。
鉴于在调节细胞状态和功能方面的核心作用,异常活动与
许多疾病,包括神经系统疾病、自身免疫、糖尿病和癌症。尤其是大师
调节因子 MYC 转录因子在超过一半的癌症中失调,但有效的治疗方法针对
MYC 驱动的基因程序尚未开发。虽然涉及直接靶向 MYC 的方法
小分子和抗体或间接靶向(例如基因沉默)已经被探索过,这些是
与主要缺点相关,包括结合相互作用或活性弱、药理学差
特性和脱靶效应。作为一种替代方法,Moellering 实验室最近开发了一种新的类
源自转录因子 MAX 的超稳定合成 DNA 结合域,正交自
二聚化以高亲和力和特异性与序列特异性结合 DNA。这些合成的转录
调节因子 (STR) 竞争性抑制 MYC/MAX 或 MAX/MAX 天然二聚体的 DNA 结合并竞争
MYC 依赖性基因表达。在此基础上,我假设这些的效力
通过共价连接分裂的单体 STR 来产生预组织的二聚体,可以增加化合物的数量
STR。此外,我假设生成多功能 STR 来招募转录机制
定向基因组位点将提供进一步的控制来抑制 MYC 依赖性表型。拟议的
研究旨在探索这两种推进 STR 技术的潜在途径并评估其效果
MYC 依赖性基因表达和表型。总之,这种串联方法将建立一个新的类别
有效的 MYC 拮抗剂,并提供研究细胞中致癌基因表达的机制工具。
此外,这种开发转录因子模拟物的模块化设计策略将为
能够准备针对其他重要转录因子和基因组的未来构建体
目标。
英文摘要
PROJECT ABSTRACT
Transcription factors are key functional proteins that regulate gene expression through direct interaction with
specific sequences of genomic DNA, thereby activating or repressing transcription. This highly conserved
process controls many central biological functions including cellular homeostasis, differentiation, and apoptosis.
Given this central role in regulating cell state and function, it is unsurprising that aberrant activity is implicated in
many diseases including neurological disorders, autoimmunity, diabetes, and cancer. In particular, the master
regulator MYC transcription factor is dysregulated in over half of all cancers, yet effective therapies targeting
MYC-driven gene programs have yet to be developed. While approaches involving direct targeting of MYC with
small molecules and antibodies or indirect targeting such as gene silencing have been explored, these are
associated with major drawbacks including weak binding interactions or activity, poor pharmacological
properties, and off-target effects. As an alternative approach, the Moellering lab recently developed a new class
of hyperstable synthetic DNA-binding domains derived from the transcription factor MAX that orthogonally self-
dimerize to sequence-specifically bind DNA with high affinity and specificity. These synthetic transcriptional
regulators (STRs) competitively inhibit the DNA binding of native dimers of MYC/MAX or MAX/MAX and contest
MYC-dependent gene expression. Building on this precedence, I hypothesize that the potency of these
compounds would be increased by covalently ligating split monomeric STRs to produce pre-organized dimeric
STRs. Additionally, I hypothesize that generating multi-functional STRs that recruit transcriptional machinery to
directed genomic sites would provide further control to inhibit MYC-dependent phenotypes. The proposed
research aims to explore these two potential routes for advancing the STR technology and evaluate their effects
on MYC-dependent gene expression and phenotypes. Together, this tandem approach will establish a new class
of potent MYC antagonists and provide mechanistic tools to study oncogenic gene expression in cells.
Additionally, this modular design strategy to develop transcription factor mimetics will provide a framework to
enable preparation of future constructs tailored towards other important transcription factors and genomic
targets.
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Targeted Gene Regulation Using Engineered Synthetic Transcriptional Regulators
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批准号:10538129
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项目类别:
-
资助金额:$6.72万
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财政年份:2022
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负责人:Colin Stuart Swenson
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依托单位:
海外基金