Reducing Cancer Transcriptional Heterogeneity through Regulation of Chromatin Structure

通过染色质结构的调节减少癌症转录异质性

基本信息

批准号：
10376877
负责人：
Vadim Backman
金额：
$ 60.71万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-09 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376877
关键词：
Adjuvant Adjuvant Therapy American Animal Model Binding Biomedical Engineering Cancer Etiology Cancerous Cell Culture Techniques Cell Death Cells Cessation of life Chemicals Chemoresistance Chromatin Chromatin Structure Colon Carcinoma Colorectal Cancer Combination Drug Therapy Complex Data Disease Disease remission Drug resistance Engineering Fostering Gene Expression Gene Expression Profile Gene Mutation Genes Genetic Transcription Genome Genomics Goals Heterogeneity Hypoxia Immune system Immunotherapy In Vitro Individual Length Malignant Neoplasms Methodology Methods Modeling Molecular Molecular Biology Multi-Drug Resistance Mutation Pattern Pharmaceutical Preparations Physical environment Play Prognosis Progression-Free Survivals Property Reaction Recurrent tumor Regulation Relapse Research Resistance Resistance development Role Sampling Solid Systems Analysis Technology Testing Therapeutic Time Transcription Process base cancer cell cancer prevention cancer subtypes cancer type carcinogenesis chemical reaction chemotherapy efficacy validation histone modification improved in vivo Model nanoenvironment nanoimaging neoplastic cell novel therapeutics patient derived xenograft model predictive modeling spatiotemporal targeted treatment tool transcriptome tumor tumor heterogeneity tumor xenograft

项目摘要

PROJECT SUMMARY Carcinogenesis involves the dysregulation, both mutational and transcriptional, of the complex interactions of hundreds of genes. Currently no platform allows for the predictable transcriptional modulation of this many genes simultaneously. Gene transcription is modulated by a number of mechanisms including the well-studied histone modification and genome compartmentalization mechanisms as well as the still insufficiently understood role of the complex physical nanoenvironment within chromatin. Since transcriptional molecular interactions are chemical reactions, they depend on the local physical environment within the chromatin which, in turn, depends on the physical pattern of chromatin folding at supra-nucleosomal length scales. The overarching goal of this project is to develop new tools to modulate the chromatin nanoenvironment for whole- scale transcriptional engineering for cancer prevention and therapeutics. Transcriptional diversity plays a major role in carcinogenesis by allowing cancer cells to explore their genomic space and has been shown to foster the emergence of resistance to chemotherapy in cancer cells. The project will leverage the methods of bioengineering to develop new tools to physico-chemically regulate chromatin structure toward a normalized, constrained, and less-adaptive state. The project will identify physico-chemical mechanisms that can be targeted to reduce transcriptional heterogeneity and validate the efficacy of the chromatin folding-normalization in patient- derived xenograft (PDX) tumor models of colon cancer as an adjuvant therapy for alleviating chemoresistance through the reduction of the transcriptional heterogeneity of tumors.

项目概要癌发生涉及复杂相互作用的突变和转录失调数百个基因。目前没有平台允许对这么多的可预测转录调节基因同时。基因转录受到多种机制的调节，包括经过充分研究的机制组蛋白修饰和基因组区室化机制以及仍然不足的了解染色质内复杂的物理纳米环境的作用。由于转录分子相互作用是化学反应，它们取决于染色质内的局部物理环境反过来，这取决于核小体上长度尺度上染色质折叠的物理模式。这该项目的总体目标是开发新工具来调节染色质纳米环境用于癌症预防和治疗的大规模转录工程。转录多样性起着通过允许癌细胞探索其基因组空间，在致癌过程中发挥主要作用，并已被证明促进癌细胞对化疗产生耐药性。该项目将利用以下方法生物工程开发新工具以物理化学方式调节染色质结构以实现标准化、受限且适应性较差的状态。该项目将确定可针对的物理化学机制减少转录异质性并验证染色质折叠正常化在患者中的功效结肠癌衍生异种移植（PDX）肿瘤模型作为缓解化疗耐药性的辅助疗法通过减少肿瘤的转录异质性。