CAREER: A Quantitative Nanosensor to Measure Redox Potential in Living Systems

职业：测量生命系统中氧化还原电位的定量纳米传感器

• 批准号: 1752506
• 负责人: Daniel Heller
• 金额: $ 50万
• 依托单位: Sloan Kettering Institute For Cancer Research
• 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: 2018-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1752506&HistoricalAwards=false
• 关键词: CAREER; Quantitative; Nanosensor; Measure; Redox

The oxidation-reduction (redox) reactions occurring in the cells and tissues of our body are essential to their proper function and have implications in aging and many diseases, including cancer. Many therapies and foods have anti-oxidant properties, but researchers have an incomplete understanding of how they might affect our cells and bodies. The aim of the project is to develop new nanotechnologies to improve the measurement of redox phenomena in cells and organisms to give a better picture of how they relate to health and disease. The principal investigator's laboratory is developing these capabilities by studying new materials with unique properties that may have big impact on many fields. Scientists, students, entrepreneurs, and even artists will work together to teach the public about these materials, make new discoveries about them, and to make them available to more people than ever before. A growing body of work in the field of cellular metabolism has shown that many fundamental biological processes are under the control of redox chemistry. Changes in redox phenomena are also implicated in many diseases, including cancer. The role of reactive species in cancer cell signaling and survival is not well-understood, however, including the roles of pro- and anti-oxidants. A large effort has started to present the basic metabolic and energetic abnormalities of cancer as a new hallmark which defines the disease. Still, the understanding of the connections between the genetic alterations in signaling pathways and the resulting complex phenotypic output of metabolism and bioenergetic changes is cursory. Current options for making redox measurements in biology fall short of the unique needs of the field. The quantification of redox potentials in living tissues would allow for measurements to be compared accurately between different laboratories. A tool sensitive to redox potentials in the cellular environment across the wider physiologic range would give researchers access to more testable hypothesis. Many fields, including diagnostics, process engineering, chemical product testing and safety, drug screening, and drug development could also benefit from the ability to measure or transmit electrochemical signals optically. In this project, the PI will develop a new class of optical reporters to measure the full-range redox potential quantitatively in live cells and organisms. The overall objective of this application is to translate the wide intrinsic voltage sensitivity and emission response of photoluminescent carbon nanotubes into biological systems. Nanotubes will be engineered for specific sensitivity across the physiologic range using new covalent and non-covalent functionalization methods to modulate nanotube emission. This approach will develop new capabilities to understand and control the near-infrared optical response of nanotubes within biological environments, as well as to modulate biological interactions of these materials to target specific sub-cellular compartments. These sensors will be used to interrogate redox landscapes in normal and diseased states, including Kras-mutant tumors. To assist with the development and dissemination of the research materials, and to teach the public about these new materials and findings with them, several initiatives are going to be implemented. The principal investigator designed a bioengineering research project to be conducted in a STEM-focused charter high school to develop methods to modulate the long-term biocompatibility of carbon nanotube sensors. The principal investigator is also working with a resident artist to use carbon nanotube-based 'nanopaints' to both educate the public and improve the availability of research materials for the nano/bioscience/art communities. A new undergraduate engineering summer program will be initiated to give engineering students the experience of working in a cancer research setting while giving faculty and trainees access to students with engineering backgrounds.

我们身体的细胞和组织中发生的氧化还原（氧化还原）反应对其正常功能至关重要，并对衰老和许多疾病（包括癌症）产生影响。许多疗法和食物都具有抗氧化特性，但研究人员对它们如何影响我们的细胞和身体还没有完全的了解。该项目的目的是开发新的纳米技术，以改善对细胞和生物体中氧化还原现象的测量，从而更好地了解它们与健康和疾病的关系。 首席研究员的实验室正在通过研究可能对许多领域产生重大影响的具有独特特性的新材料来开发这些能力。科学家、学生、企业家，甚至艺术家将共同努力，向公众介绍这些材料，对它们进行新的发现，并使它们比以往任何时候都更容易被更多的人使用。在细胞代谢领域中，越来越多的工作表明，许多基本的生物过程都受到氧化还原化学的控制。氧化还原现象的变化也涉及许多疾病，包括癌症。然而，活性物质在癌细胞信号传导和存活中的作用还没有得到很好的理解，包括促氧化剂和抗氧化剂的作用。大量的努力已经开始提出癌症的基本代谢和能量异常作为定义疾病的新标志。尽管如此，对信号通路中的遗传改变与代谢和生物能量变化的复杂表型输出之间的联系的理解仍然是粗略的。目前在生物学中进行氧化还原测量的选择不能满足该领域的独特需求。活组织中氧化还原电位的定量将允许在不同实验室之间准确地比较测量结果。一种对细胞环境中更广泛的生理范围内的氧化还原电位敏感的工具将使研究人员能够获得更可验证的假设。许多领域，包括诊断、工艺工程、化学产品测试和安全、药物筛选和药物开发，也可以从光学测量或传输电化学信号的能力中受益。在这个项目中，PI将开发一类新的光学报告分子，以定量测量活细胞和生物体的全范围氧化还原电位。本申请的总体目标是将光致发光碳纳米管的宽固有电压灵敏度和发射响应转化为生物系统。将使用新的共价和非共价官能化方法来调节纳米管发射，以使纳米管在生理范围内具有特定的灵敏度。这种方法将开发新的能力来理解和控制生物环境中纳米管的近红外光学响应，以及调节这些材料的生物相互作用以靶向特定的亚细胞区室。这些传感器将用于询问正常和患病状态下的氧化还原景观，包括Kras突变肿瘤。为了协助编写和传播研究材料，并向公众介绍这些新材料和研究结果，将实施若干举措。首席研究员设计了一个生物工程研究项目，将在一所以STEM为重点的特许高中进行，以开发调节碳纳米管传感器长期生物相容性的方法。首席研究员还与一位常驻艺术家合作，使用基于碳纳米管的“纳米涂料”来教育公众，并提高纳米/生物科学/艺术社区研究材料的可用性。一个新的本科工程暑期项目将启动，让工程专业的学生在癌症研究环境中工作的经验，同时让教师和学员获得工程背景的学生。

项目成果

An in Vivo Nanosensor Measures Compartmental Doxorubicin Exposure

• DOI: 10.1021/acs.nanolett.9b00956
• 发表时间: 2019-07-01
• 期刊: NANO LETTERS
• 影响因子: 10.8
• 作者: Harvey, Jackson D.;Williams, Ryan M.;Heller, Daniel A.
• 通讯作者: Heller, Daniel A.

En route to single-step, two-phase purification of carbon nanotubes facilitated by high-throughput spectroscopy.

• DOI: 10.1038/s41598-021-89839-4
• 发表时间: 2021-05-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Podlesny B;Olszewska B;Yaari Z;Jena PV;Ghahramani G;Feiner R;Heller DA;Janas D
• 通讯作者: Janas D

Glutathione-S-transferase Fusion Protein Nanosensor.

• DOI: 10.1021/acs.nanolett.0c02691
• 发表时间: 2020-10-14
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Williams RM;Harvey JD;Budhathoki-Uprety J;Heller DA
• 通讯作者: Heller DA

An optical nanoreporter of endolysosomal lipid accumulation reveals enduring effects of diet on hepatic macrophages in vivo.

• DOI: 10.1126/scitranslmed.aar2680
• 发表时间: 2018-10-03
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Galassi TV;Jena PV;Shah J;Ao G;Molitor E;Bram Y;Frankel A;Park J;Jessurun J;Ory DS;Haimovitz-Friedman A;Roxbury D;Mittal J;Zheng M;Schwartz RE;Heller DA
• 通讯作者: Heller DA

Electrostatic Screening Modulates Analyte Binding and Emission of Carbon Nanotubes

• DOI: 10.1021/acs.jpcc.8b01239
• 发表时间: 2018-05-17
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY C
• 影响因子: 3.7
• 作者: Harvey, Jackson D.;Zerze, Gul H.;Heller, Daniel A.
• 通讯作者: Heller, Daniel A.