Collaborative Research: Manipulating Epigenetic Mechanisms to Enhance Non-Viral Transgene Expression
合作研究:操纵表观遗传机制以增强非病毒转基因表达
基本信息
- 批准号:1404084
- 负责人:
- 金额:$ 42.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:Standard Grant
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-01 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
CBET - 1404084/1403214Rege/ElmerDNA or gene delivery to mammalian cells has several applications in biotechnology and medicine. However, the activation of foreign genes (transgenes), and subsequent efficacy of protein expression from them, is often hindered by defense mechanisms inside the host cell. For example, cells are able to control transgene protein expression by either burying existing genes inside condensed chromosomes in the nucleus in order to turn them off, or by relaxing chromosomes in order to expose genes and activate them. A family of 'epigenetic' enzymes present within cells typically controls these processes of gene regulation; enzymes that activate genes are generally classified as activators, while those that turn genes off are called repressors. In the proposed research, the investigators will study the role of these epigenetic enzymes in regulating the expression from delivered transgenes. Furthermore, tools from the emerging field of synthetic biology will be employed to design novel DNA sequences and activator enzymes that enhance protein expression from delivered transgenes. Findings from these studies will have a transformative impact on biotechnology processes and medical treatments (e.g. gene therapy) that utilize DNA or gene delivery to mammalian cells. Outreach from this project will reach K-12 students through a PCR-based molecular biology project facilitated by the Quanta program at ASU. The proposed outreach will be designed to increase participation of students from underrepresented populations in STEM activities in Arizona and Pennsylvania.In the same way that words are neatly organized in the pages of books in a library, cellular genes are condensed by histone proteins to form chromosomes in the nucleus. Epigenetic regulation, mediated by several enzymes, plays a key role in controlling gene expression inside cells. Since recent work has shown that epigenetic mechanisms can silence viral genes, it is likely that epigenetics may also regulate the expression of foreign genes (i.e. transgenes) that are delivered in the form of plasmid DNA to mammalian cells. The goal of this project is to manipulate intracellular epigenetic enzymes in order to enhance transgene expression by (1) using drugs to inhibit repressors and to prevent the deactivation of transgenes, (2) adding designed DNA sequences to the plasmids in order to recruit activator enzymes, and (3) using principles from synthetic biology in order to design and validate novel epigenetic activator enzymes that can selectively bind transgenes and enhance their expression. These approaches will deepen our understanding of epigenetic mechanisms that regulate protein expression from foreign transgenes (plasmid DNA) in human cells, leading to increased efficacy of gene therapy treatments in medicine, and cellular engineering approaches in biotechnology.This award is co-funded by the Biotechnology, Biochemical, and Biomass Engineering Program of the CBET Division and by the Systems and Synthetic Biology Program of the Division of Molecular and Cellular Biology.
CBET-1404084/1403214Rege/ElmerDNA或基因递送到哺乳动物细胞在生物技术和医学中有几个应用。然而,外源基因(转基因)的激活以及由此产生的蛋白质表达的有效性往往受到宿主细胞内防御机制的阻碍。例如,细胞能够控制转基因蛋白质的表达,要么将现有的基因埋在细胞核的浓缩染色体中以关闭它们,要么通过放松染色体以暴露基因并激活它们。存在于细胞内的一系列“表观遗传”酶通常控制着这些基因调控过程;激活基因的酶通常被归类为激活物,而那些关闭基因的酶被称为阻遏物。在这项拟议的研究中,研究人员将研究这些表观遗传酶在调节转基因表达方面的作用。此外,来自新兴合成生物学领域的工具将被用于设计新的DNA序列和激活酶,以增强所传递的转基因的蛋白质表达。这些研究的结果将对利用DNA或基因输送到哺乳动物细胞的生物技术进程和医疗(例如基因治疗)产生革命性的影响。该项目将通过亚利桑那州立大学广达项目促进的基于聚合酶链式反应的分子生物学项目,惠及K-12年级的学生。拟议的外展将旨在增加亚利桑那州和宾夕法尼亚州来自代表性不足人群的学生对STEM活动的参与。就像图书馆的书籍页面中整齐地组织单词一样,细胞基因由组蛋白浓缩在细胞核中形成染色体。表观遗传调控由多种酶介导,在控制细胞内基因表达方面起着关键作用。由于最近的工作表明,表观遗传机制可以沉默病毒基因,很可能表观遗传学也可能调节以质粒DNA形式传递给哺乳动物细胞的外源基因(即转基因)的表达。本项目的目标是通过以下方式操纵细胞内的表观遗传酶以提高转基因的表达:(1)使用药物抑制抑制物并防止转基因失活;(2)将设计的DNA序列添加到质粒中以招募激活酶;以及(3)利用合成生物学的原理来设计和验证能够选择性结合转基因并增强其表达的新型表观遗传激活酶。这些方法将加深我们对调控外源转基因(质粒DNA)在人类细胞中蛋白质表达的表观遗传机制的理解,从而提高医学上的基因治疗方法的有效性,以及生物技术中的细胞工程方法。该奖项由CBET部门的生物技术、生化和生物量工程计划以及分子和细胞生物学部门的系统和合成生物学计划共同资助。
项目成果
期刊论文数量(0)
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Kaushal Rege其他文献
Histamine receptor agonism differentially induces immune and reparative healing responses in biomaterial-facilitated tissue repair
- DOI:
10.1016/j.biomaterials.2024.122967 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:
- 作者:
Jordan R. Yaron;Shubham Pallod;Nicole Grigaitis-Esman;Vanshika Singh;Samantha Rhodes;Dirghau Manishbhai Patel;Deepanjan Ghosh;Kaushal Rege - 通讯作者:
Kaushal Rege
Correction to: Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer
- DOI:
10.1007/s11095-018-2488-0 - 发表时间:
2018-09-05 - 期刊:
- 影响因子:4.300
- 作者:
Nishant S. Gandhi;Sudhakar Godeshala;Dana-Lynn T. Koomoa-Lange;Bhavani Miryala;Kaushal Rege;Mahavir B. Chougule - 通讯作者:
Mahavir B. Chougule
Amino Acid Templated Plasmonic Nanosensor for Radiation Gel Dosimetry
- DOI:
10.1016/j.bpj.2019.11.2007 - 发表时间:
2020-02-07 - 期刊:
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Subhadeep Dutta;Karthik Pushpavanam;Tomasz Bista;Eric Boshoven;Stephen Sapareto;Kaushal Rege - 通讯作者:
Kaushal Rege
Biogenic Silica Nanopore Membranes on Micromachined Silicon Substrates
- DOI:
10.1016/j.bpj.2011.11.1110 - 发表时间:
2012-01-31 - 期刊:
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- 作者:
Michael Goryll;Kai-Chun Lin;Xiaofeng Wang;Shankar Ramakrishnan;Sandwip K. Dey;Kaushal Rege;B.L. Ramakrishna - 通讯作者:
B.L. Ramakrishna
Kaushal Rege的其他文献
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{{ truncateString('Kaushal Rege', 18)}}的其他基金
Collaborative Research: Molecular engineering of Methylation-Specific Binding Agents for DNA Purification
合作研究:用于 DNA 纯化的甲基化特异性结合剂的分子工程
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1836525 - 财政年份:2018
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Continuing Grant
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1706268 - 财政年份:2017
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COLLABORATIVE RESEARCH: Polypeptide-Templated Nanoparticles as Colorimetric Sensors of Ionizing Radiation
合作研究:多肽模板纳米粒子作为电离辐射比色传感器
- 批准号:
1403860 - 财政年份:2014
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Standard Grant
Collaborative Research: Designing Multivalent Ligands for Plasmid DNA Purification
合作研究:设计用于质粒 DNA 纯化的多价配体
- 批准号:
1067840 - 财政年份:2011
- 资助金额:
$ 42.64万 - 项目类别:
Standard Grant
Biocompatible Metal (Core)-Layered Double Hydroxide (Shell) Nanoparticles for siRNA Delivery
用于 siRNA 递送的生物相容性金属(核)层状双氢氧化物(壳)纳米粒子
- 批准号:
0829128 - 财政年份:2008
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$ 42.64万 - 项目类别:
Standard Grant
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