EFRI CEE : Engineering Technologies to Determine Causal Relationships Between Chromatin Structure and Gene Regulation

EFRI CEE：确定染色质结构与基因调控之间因果关系的工程技术

• 批准号: 1830957
• 负责人: Charles Gersbach
• 金额: $ 200万
• 依托单位: Duke 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: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1830957&HistoricalAwards=false
• 关键词: EFRI; CEE; Engineering; Technologies; Determine

The structure of the human genome inside of a living cell is precisely and dynamically controlled to determine the level of each gene in different cell types, in response to environmental stimuli, and in various disease conditions. The chemical modification and three-dimensional folding of our DNA plays an even greater role than our inherited genetics in human development, disease progression, and drug response. There have been tremendous advances in mapping genome sequence and structure but our understanding of the relationship between genome structure and function is relatively poor. The objective of this proposal is to cross interdisciplinary boundaries to develop the necessary technologies to accurately predict, quantitatively monitor, and deterministically program genome structure to generate improved disease models that will catalyze transformative drug development. The team will also develop educational programs to inspire the next generation of scientists in this emerging discipline.Innovative new technologies, including reporters of dynamic molecular structure and CRISPR/Cas9-based epigenome editing, provide a unique opportunity to monitor and perturb epigenetic states that govern chromatin structure. The team will generate new molecular tools for monitoring changes to epigenetic states in live cells using FRET-based nanosensors that report on structural changes to chromatin structure and mechanics in response to targeted perturbations by CRISPR/Cas9-based epigenome editing. This data will inform molecular models that predict the effect of epigenetic changes on chromatin structure and consequent changes in gene expression. These technologies and models will be validated in the context of human tumor models to illuminate the relationship between chromatin structure and cancer progression. Collectively, this will enable the development of new technologies and models that are broadly useful for disease modeling and drug screening.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.

活细胞内的人类基因组结构受到精确和动态控制，以确定不同细胞类型中每个基因的水平，以响应环境刺激和各种疾病状况。我们DNA的化学修饰和三维折叠在人类发育、疾病进展和药物反应中发挥的作用甚至比我们的遗传基因更大。基因组序列和结构的绘制已经取得了巨大的进展，但我们对基因组结构和功能之间的关系的理解相对较差。该提案的目标是跨越跨学科界限，开发必要的技术来准确预测，定量监测和确定性地编程基因组结构，以生成改进的疾病模型，从而促进变革性药物开发。该团队还将开发教育项目，以激励这一新兴学科的下一代科学家。创新的新技术，包括动态分子结构报告和基于CRISPR/Cas9的表观基因组编辑，为监测和扰乱控制染色质结构的表观遗传状态提供了独特的机会。该团队将使用基于FRET的纳米传感器生成新的分子工具，用于监测活细胞中表观遗传状态的变化，这些纳米传感器报告染色质结构和力学的结构变化，以响应基于CRISPR/Cas9的表观基因组编辑的靶向扰动。这些数据将为预测表观遗传变化对染色质结构的影响以及随之而来的基因表达变化的分子模型提供信息。这些技术和模型将在人类肿瘤模型的背景下进行验证，以阐明染色质结构与癌症进展之间的关系。总的来说，这将使新技术和模型的发展，广泛用于疾病建模和药物筛选。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

项目成果

Nonlinear Shear Rheology of Entangled Polymer Rings

• DOI: 10.1021/acs.macromol.0c02839
• 发表时间: 2021-03
• 期刊: Macromolecules
• 影响因子: 5.5
• 作者: D. Parisi;S. Costanzo;Youncheol Jeong;Junyoung Ahn;T. Chang;D. Vlassopoulos;J. Halverson;K. Kremer;T. Ge;M. Rubinstein;G. Grest;Watee Srinin;A. Grosberg

Structure of Polymer-Grafted Nanoparticle Melts.

• DOI: 10.1021/acsnano.0c06134
• 发表时间: 2020-11-24
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Midya J;Rubinstein M;Kumar SK;Nikoubashman A
• 通讯作者: Nikoubashman A

Mobility of Polymer-Tethered Nanoparticles in Unentangled Polymer Melts

• DOI: 10.1021/acs.macromol.8b02138
• 发表时间: 2019-02-26
• 期刊: MACROMOLECULES
• 影响因子: 5.5
• 作者: Ge, Ting;Rubinstein, Michael
• 通讯作者: Rubinstein, Michael

Master Regulators and Cofactors of Human Neuronal Cell Fate Specification Identified by CRISPR Gene Activation Screens.

• DOI: 10.1016/j.celrep.2020.108460
• 发表时间: 2020-12-01
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Black JB;McCutcheon SR;Dube S;Barrera A;Klann TS;Rice GA;Adkar SS;Soderling SH;Reddy TE;Gersbach CA
• 通讯作者: Gersbach CA

Myogenic Progenitor Cell Lineage Specification by CRISPR/Cas9-Based Transcriptional Activators

• DOI: 10.1016/j.stemcr.2020.03.026
• 发表时间: 2020-05-12
• 期刊: STEM CELL REPORTS
• 影响因子: 5.9
• 作者: Kwon, Jennifer B.;Vankara, Ashish;Gersbach, Charles A.
• 通讯作者: Gersbach, Charles A.