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EFRI CEE: Human cardiac opto-epigenetics with HDAC inhibitors

EFRI CEE：HDAC 抑制剂的人类心脏光表观遗传学

基本信息

批准号：
1830941
负责人：
Emilia Entcheva
金额：
$ 200万
依托单位：
George Washington University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1830941&HistoricalAwards=false
关键词：
EFRI CEE Human cardiac opto

项目摘要

Predisposition to disease and reaction to drugs only partially depend on our genetic code. The organization, packing and subtle dynamic interactions of the DNA in the cell nucleus can profoundly modify gene expression and affect human health. The DNA packing and dynamics can be altered by factors and molecules known as epigenetic modifiers of gene expression and are of great interest in oncology and cardiology. The overall goal in this EFRI project is to obtain better understanding of the action of the dynamic chromatin modifiers in heart cells to inspire new therapies at the intersection of oncology and cardiology and help develop safer and more effective drugs. The team will deploy new optical techniques and light-sensitive tools to address this challenge. Histone deacetylase inhibitors (HDACi) represent a class of powerful chromatin modifiers. Active development of HDACi as therapeutic agents has yielded over 500 small molecules, currently at different stages of clinical trials. The team will leverage a key feature of HDAC-mediated control of the chromatin structure, namely its fast dynamics and reversibility compared to other repressive chromatin regulators. They will develop a new framework and technology for linking epigenetic modulation to phenotype, and apply it to human stem-cell-derived cardiomyocytes subjected to environmental stressors. Photoswitchable small molecules (HDACi) and patterned light are used to imprint a dynamic epigenetic modification in time-space. Optically-gated high-pressure freezing will temporally-resolved precise registration of the immediate HDACi-mediated chromatin modulation, imaged by electron microscopy. Documenting the sequence of events, triggered by the epigenetic master-regulators of cell function, will have a broad impact for fundamental understanding of biological function, namely how does the genome re-arrangement link to phenotype under different stressors.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

对疾病的易感性和对药物的反应只部分取决于我们的遗传密码。细胞核内DNA的组织、包装和微妙的动态相互作用可以深刻地改变基因表达，影响人类健康。DNA的包装和动力学可以被称为基因表达的表观遗传修饰因子的因素和分子所改变，这在肿瘤学和心脏病学中引起了极大的兴趣。EFRI项目的总体目标是更好地了解动态染色质修饰剂在心脏细胞中的作用，以激发肿瘤学和心脏病学交叉领域的新疗法，并帮助开发更安全、更有效的药物。该团队将采用新的光学技术和光敏感工具来解决这一挑战。组蛋白去乙酰化酶抑制剂（HDACi）是一类功能强大的染色质修饰剂。HDACi作为治疗药物的积极开发已经产生了500多个小分子，目前处于不同的临床试验阶段。该团队将利用hdac介导的染色质结构控制的一个关键特征，即与其他抑制性染色质调节因子相比，其快速动态和可逆性。他们将开发一种新的框架和技术，将表观遗传调节与表型联系起来，并将其应用于受到环境压力的人类干细胞来源的心肌细胞。光开关小分子（HDACi）和图案光被用来在时空上刻印动态表观遗传修饰。光学门控高压冷冻将暂时解决精确注册即时hdac介导的染色质调制，通过电子显微镜成像。记录由细胞功能的表观遗传主调控因子触发的事件序列，将对生物学功能的基本理解产生广泛的影响，即基因组重排如何与不同应激源下的表型联系起来。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。