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Targeted Gene Regulation Using Engineered Synthetic Transcriptional Regulators

使用工程合成转录调节剂进行靶向基因调节

基本信息

批准号：
10729851
负责人：
Colin Stuart Swenson
金额：
$ 6.95万
依托单位：
UNIVERSITY OF CHICAGO
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：
https://reporter.nih.gov/project-details/10729851
关键词：
Affect Affinity Antibodies Apoptosis Autoimmunity Binding Binding Proteins Binding Sites Biological Process Biological Products Breathing Cells Characteristics Chimeric Proteins Chromatin Structure DNA DNA Binding DNA Binding Domain DNA-Protein Interaction Diabetes Mellitus Dimerization Disease Engineering Enhancers Functional disorder Future Gene Expression Gene Expression Regulation Gene Silencing Generations Genes Genetic Transcription Genome Genomic DNA Genomics Homeostasis Investigation Lead Libraries Ligation Link Malignant Neoplasms Mediating Nature Oncogenic Permeability Phenotype Preparation Process Promoter Regions Property Proteins Proto-Oncogene Proteins c-myc RNA Research Role Route Site Solubility Specificity Structure Technology Testing Therapeutic antagonist clinically relevant cofactor design dimer drug discovery effective therapy empowerment gene repression improved innovation lead optimization mimetics monomer nervous system disorder novel strategies pharmacologic programs promoter rational design recruit small molecule success synthetic construct targeted treatment therapeutically effective tool transcription factor

项目摘要

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.

项目摘要