CAREER: High bandwidth nano-transistors to understand the kinetic basis for CRISPR/CAS enzymes to enhance their applications for diagnostics and therapeutics

职业:高带宽纳米晶体管,以了解 CRISPR/CAS 酶的动力学基础,以增强其在诊断和治疗方面的应用

基本信息

  • 批准号:
    2048283
  • 负责人:
  • 金额:
    $ 54.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-02-15 至 2024-05-31
  • 项目状态:
    已结题

项目摘要

The knowledge of how biological molecules interact with each other is essential to understanding their roles in sustaining life. Molecular interactions are commonly measured using optical techniques and specialized optical labels on the molecules of interest. Recent advances in modern electronics and nanoscale materials potentially allow continuous monitoring of molecular interactions in a more natural state without optical labels and instruments. The goal of this CAREER project is to develop a single-molecule high-speed nanoelectronic platform to better understand the function of CRISPR (clustered regularly interspaced short palindromic repeats)-associated enzymes known as "molecular scissors". These enzymes allow gene editing and have revolutionized many basic and applied research areas. The knowledge gained will be beneficial for many applications in CRISPR engineering, pharmaceutical drug discovery, clinical diagnostics, and agricultural science. The project will promote early research involvement and mentorship opportunities to a new generation of engineers and scientists pursuing a career of interdisciplinary research intersecting modern biology, nanotechnology and engineering.The investigator’s scientific career vision is to explore the utility of nano-electronic systems to develop transformative and customizable biosensing platforms for pharmaceutical, clinical, and environmental applications. As part of this vision, this project focuses on the integration of CRISPR (clustered regularly interspaced short palindromic repeats) with high bandwidth graphene field effect transistors (gFETs) designed for single-molecule sensing. The platform provides unique electronic signatures representing the molecular interactions that happen concurrently between the CRISPR and target DNA/RNA at different timescales. The CRISPR-Cas system is a family of RNA guided enzymes that is widely used for gene editing as it is capable of double-stranded DNA binding and cleavage, producing insertions and deletions (INDELs) at specific loci within the genome in vivo. The application areas of CRISPR technology are rapidly extending beyond genome editing, such as targeted gene regulation, in vivo imaging, epigenetic modulation as well as nucleic acid detection for diagnostic applications. The goal of this CAREER proposal is to provide a tool to evaluate the enzymatic activity of newly discovered or engineered CRISPR-Cas enzymes to better understand their biology and the impact of CRISPR-Cas mutagenesis, guide RNA modifications as well as genetic variation of the target on their functions. Successful development of the single molecule high bandwidth gFET for CRISPR analysis coupled with trained machine learning models, will provide a tool for detailed analysis of the CRISPR interactions with its target sequence in terms of binding, cleavage, and release of the target in real-time as well as identification of the variables most important for predicting CRISPR function. The information obtained can direct the design and optimization of CRISPR-Cas enzymes toward enhancing their efficiency and safety in wide range of applications. The applications of the single-molecule high bandwidth gFET platform can be expanded for understanding the molecular interactions of other enzymes beyond CRISPR.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.
了解生物分子如何相互作用,对于理解它们在维持生命中所扮演的角色至关重要。分子之间的相互作用通常是用光学技术和专门的光学标签来测量的。现代电子学和纳米级材料的最新进展有可能在没有光学标签和仪器的情况下,在更自然的状态下连续监测分子相互作用。CAREER项目的目标是开发一种单分子高速纳米电子平台,以更好地了解被称为“分子剪刀”的CRISPR(聚集规律间隔短回文重复序列)相关酶的功能。这些酶使基因编辑成为可能,并使许多基础和应用研究领域发生了革命性的变化。所获得的知识将有助于CRISPR工程,药物发现,临床诊断和农业科学的许多应用。该项目将促进新一代工程师和科学家的早期研究参与和指导机会,这些工程师和科学家从事交叉现代生物学、纳米技术和工程学的跨学科研究。研究者的科学职业愿景是探索纳米电子系统的效用,为制药、临床和环境应用开发变革性和可定制的生物传感平台。作为这一愿景的一部分,该项目专注于将CRISPR(定期间隔聚集的短回文重复序列)与专为单分子传感设计的高带宽石墨烯场效应晶体管(gfet)集成在一起。该平台提供了独特的电子签名,代表了在不同时间尺度上CRISPR和目标DNA/RNA之间同时发生的分子相互作用。CRISPR-Cas系统是一个RNA引导酶家族,由于它能够在体内双链DNA结合和切割,在基因组的特定位点上产生插入和缺失(INDELs),被广泛用于基因编辑。CRISPR技术的应用领域正在迅速扩展到基因组编辑以外的领域,如靶向基因调控、体内成像、表观遗传调控以及用于诊断的核酸检测。本CAREER提案的目标是提供一种工具来评估新发现或工程化的CRISPR-Cas酶的酶活性,以更好地了解其生物学和CRISPR-Cas诱变的影响,指导RNA修饰以及目标基因变异对其功能的影响。成功开发用于CRISPR分析的单分子高带宽gFET与训练有素的机器学习模型相结合,将为详细分析CRISPR与其靶序列在结合、切割和释放靶标方面的相互作用以及识别预测CRISPR功能最重要的变量提供工具。获得的信息可以指导CRISPR-Cas酶的设计和优化,以提高其在广泛应用中的效率和安全性。单分子高带宽gFET平台的应用可以扩展到理解CRISPR之外的其他酶的分子相互作用。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。

项目成果

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Kiana Aran其他文献

Microfiltration device for continuous, label-free bacteria separation from whole blood for sepsis treatment
微滤装置,用于从全血中连续、无标记地分离细菌,用于脓毒症治疗
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kiana Aran;M. C. Morales;Lawrence A. Sasso;J. Lo;Mingde Zheng;I. H. Johnston;Neal Kamdar;A. Ündar;J. Zahn
  • 通讯作者:
    J. Zahn
Development of microfluidic platform for continuous extraction of diagnostics plasma proteins from whole blood during cardiac surgery
开发微流体平台,用于在心脏手术期间从全血中连续提取诊断血浆蛋白
A turn‐off fluorescent substrate for horseradish peroxidase improves the sensitivity of ELISAs
辣根过氧化物酶的关闭荧光底物可提高 ELISA 的灵敏度
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    A. Acharya;Payel Sen;Kiana Aran;Austin B. Gardner;Mohammad Rafi;Deborah Dean;N. Murthy
  • 通讯作者:
    N. Murthy
CRISPR quality control on a chip
芯片上的 CRISPR 质量控制
  • DOI:
    10.1038/s44222-024-00159-4
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kiana Aran;Brett R. Goldsmith
  • 通讯作者:
    Brett R. Goldsmith
Machine Learning for Disease Classification: A Perspective
用于疾病分类的机器学习:一个视角

Kiana Aran的其他文献

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{{ truncateString('Kiana Aran', 18)}}的其他基金

CAREER: High bandwidth nano-transistors to understand the kinetic basis for CRISPR/CAS enzymes to enhance their applications for diagnostics and therapeutics
职业:高带宽纳米晶体管,以了解 CRISPR/CAS 酶的动力学基础,以增强其在诊断和治疗方面的应用
  • 批准号:
    2427540
  • 财政年份:
    2023
  • 资助金额:
    $ 54.95万
  • 项目类别:
    Continuing Grant

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CAREER: High bandwidth nano-transistors to understand the kinetic basis for CRISPR/CAS enzymes to enhance their applications for diagnostics and therapeutics
职业:高带宽纳米晶体管,以了解 CRISPR/CAS 酶的动力学基础,以增强其在诊断和治疗方面的应用
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