Collaborative Research: L-RNA Based Reactive Oxygen Species Detection and Response Systems

合作研究：基于L-RNA的活性氧检测和响应系统

• 批准号: 2003534
• 负责人: Jeremiah Gassensmith
• 金额: $ 40.11万
• 依托单位: University of Texas at Dallas
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2003534&HistoricalAwards=false
• 关键词: Collaborative; Research; RNA; Based; Reactive

Non-Technical Summary: Radiation therapy (radiotherapy) has been used to treat cancer for more than 100 years and new clinical innovations have allowed for very focused beams of radiation to kill malignant cells. These beams are made of high energy light particles that enter the body and cause water and oxygen to react and split into many different reactive oxygen species (ROS). These ROS then go on to destroy the genetic material inside a cell, which ultimately leads to the cell’s death. In cancer treatment, radiotherapy is usually not completely effective on its own. Sometimes it misses cancerous cells. Sometimes there’s not enough oxygen for it to create the therapeutic ROS. In fact, it is almost impossible to tell if it is working until a follow up appointment. Because radiation is composed of such high energy particles, not very many molecules directly interact with it; however, it is known that radiation kills cells because genetic material is so susceptible to chemical reactions with these ROS. It makes sense then that a molecular probe made from genetic material should be able to respond to radiation damage. This proposal focuses on designing new artificial biomaterial-based sensors that “look” almost exactly like the genetic material in your body except cells can’t read it like normal RNA or DNA and it won’t be degraded by enzymes in the body yet radiation affects it the exact same way. These new probes will be designed to target the mitochondria or the “powerhouse of the cell” to identify how radiation causes damage to cells. Finally, this work proposes to make a new type of nanomaterial that can glow when it is hit by radiation. One day, this sort of material might be able to tell doctors in real time if radiotherapy is working.Technical Summary: The overproduction of reactive oxygen species (ROS) damages genetic material, causing cell death. The causes of ROS overproduction are various and range from mitochondrial dysfunction to radiation exposure. Hydroxy radicals—reactive •OH—cannot be eliminated by enzymatic reactions and are uniquely powerful enough to induce single strand breaks in RNA and DNA. Understanding the chemistry of •OH is essential to address fundamental challenges in a number of arenas at the cellular and tissue levels. Several •OH sensitive fluorescent probes exist but they lack the sensitivity to detect the single digit μM concentrations in cells and/or cannot distinguish between •OH and other ROS. Thus, detecting or exploiting •OH—one of the most pernicious ROS—is hamstrung by a lack of adequate tools. The objective in this proposal is to optimize new L-RNA oligomers as a biorthogonal tool that can undergo strand scission “triggered” by •OH. The research team will show these optimized L-RNA can be synthetically tailored to target cellular organelles to report on •OH concentrations. Finally, L-RNA strand scission will be triggered as a nano-formulation in the presence of ROS to make a highly selective “smart” material. The central hypothesis is that L-RNA will undergo single strand cleavage at physiologically relevant •OH concentrations, is non-toxic, and will not be enzymatically destroyed in vitro or in vivo. At the conclusion of this proof-of-concept study, the expected outcome will be the validation of L-RNA as a long-lived and targetable sensor in vitro. The groundwork laid here will be further enabling in the development of new “biorthogonal” DNA and RNA architectures that can work in vivo and in vitro.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.

非技术总结：放射疗法（放疗）用于治疗癌症已有100多年的历史，新的临床创新允许非常聚焦的辐射束杀死恶性细胞。这些光束是由高能光粒子组成的，这些粒子进入人体，使水和氧气发生反应并分裂成许多不同的活性氧（ROS）。这些ROS然后继续破坏细胞内的遗传物质，最终导致细胞死亡。在癌症治疗中，放疗本身通常并不完全有效。有时会漏掉癌细胞。有时没有足够的氧气来产生治疗性活性氧。事实上，在后续预约之前，几乎不可能知道它是否有效。由于辐射是由这样的高能粒子组成的，没有太多的分子直接与它相互作用;然而，众所周知，辐射杀死细胞是因为遗传物质对这些ROS的化学反应非常敏感。因此，由遗传物质制成的分子探针应该能够对辐射损伤做出反应，这是有道理的。这项提案的重点是设计新的基于人工生物材料的传感器，这些传感器“看起来”几乎完全像你体内的遗传物质，除了细胞不能像正常的RNA或DNA那样读取它，而且它不会被体内的酶降解，但辐射会以完全相同的方式影响它。这些新的探针将被设计成靶向线粒体或“细胞的发电站”，以确定辐射如何对细胞造成损害。最后，这项工作提出了一种新型的纳米材料，当它被辐射击中时可以发光。总有一天，这种材料可能会真实的告诉医生放射治疗是否有效。技术总结：活性氧（ROS）的过度产生会破坏遗传物质，导致细胞死亡。ROS过量产生的原因是多种多样的，范围从线粒体功能障碍到辐射暴露。羟基自由基-反应性·OH-不能通过酶促反应消除，并且具有独特的强大功能，足以诱导RNA和DNA的单链断裂。了解·OH的化学性质对于解决细胞和组织水平上许多领域的根本挑战至关重要。存在几种·OH敏感的荧光探针，但它们缺乏检测细胞中单位数μM浓度的灵敏度和/或不能区分·OH和其他ROS。因此，检测或利用·OH-最有害的ROS之一-由于缺乏足够的工具而受到阻碍。本提案的目的是优化新的L-RNA寡聚体作为双正交工具，可以通过·OH“触发”链断裂。研究小组将展示这些优化的L-RNA可以合成定制以靶向细胞器，以报告·OH浓度。最后，L-RNA链断裂将在ROS存在下作为纳米制剂被触发，以制造高度选择性的“智能”材料。中心假设是L-RNA在生理相关的·OH浓度下会发生单链切割，无毒，并且在体外或体内不会被酶促破坏。 在这项概念验证研究结束时，预期的结果将是验证L-RNA作为体外长寿命和可靶向的传感器。该奖项反映了NSF的法定使命，并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，被认为值得支持。

项目成果

Virus-like particles: a self-assembled toolbox for cancer therapy

• DOI: 10.1016/j.mtchem.2022.100808
• 发表时间: 2022-03-01
• 期刊: MATERIALS TODAY CHEMISTRY
• 影响因子: 7.3
• 作者: Shahrivarkevishahi，A.;Hagge，L. M.;Gassensmith，J. J.
• 通讯作者: Gassensmith，J. J.

PhotothermalPhage: A Virus-Based Photothermal Therapeutic Agent

光热噬菌体：一种基于病毒的光热治疗剂

• DOI: 10.1021/jacs.1c05090
• 发表时间: 2021
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Shahrivarkevishahi, Arezoo;Luzuriaga, Michael A.;Herbert, Fabian C.;Tumac, Alisia C.;Brohlin, Olivia R.;Wijesundara, Yalini H.;Adlooru, Abhinay V.;Benjamin, Candace;Lee, Hamilton;Parsamian, Perouza
• 通讯作者: Parsamian, Perouza

Zeolitic Imidazolate Framework Nanoencapsulation of CpG for Stabilization and Enhancement of Immunoadjuvancy

• DOI: 10.1021/acsanm.1c03555
• 发表时间: 2022-01-12
• 期刊: ACS APPLIED NANO MATERIALS
• 影响因子: 5.9
• 作者: Brohlin, Olivia R.;Ehrman, Ryanne N.;Gassensmith, Jeremiah J.
• 通讯作者: Gassensmith, Jeremiah J.

Expanding Inclusivity with Learner-Generated Study Aids in Three Different Science Courses

• DOI: 10.1021/acs.jchemed.1c00373
• 发表时间: 2021-09-28
• 期刊: JOURNAL OF CHEMICAL EDUCATION
• 影响因子: 3
• 作者: Piontkivska, Helen;Gassensmith, Jeremiah J.;Gallardo-Williams, Maria T.
• 通讯作者: Gallardo-Williams, Maria T.

Strong π-stacking causes unusually large anisotropic thermal expansion and thermochromism

• DOI: 10.1073/pnas.2106572118
• 发表时间: 2021-11-01
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Dharmarwardana, Madushani;Otten, Brooke M.;Omary, Mohammad A.
• 通讯作者: Omary, Mohammad A.