ERI: Nanoscale Photo-Magnetic Energy Transfer Modulation to Restore the Homeostatic Functioning of the Damaged Endothelium

内皮细胞排列在血管壁上，在各种情况下，包括糖尿病和各种炎症性疾病，都会受到显著的压力。这种情况大大增加了与高发病率和死亡率相关的心血管疾病的风险。目前的非侵入性方法缺乏有效和有针对性的损伤修复。光疗法，当通过特定的辐射模式进行管理时，可以提取显着的优势，因此，通常被认为是再生医学中的一种非侵入性治疗方法。由具有磁性的材料制成的纳米结构是设计类似应用的新平台的诱人可能性。因此，通过适当地结合光激发和磁激发进行组织修复，有可能提高这些方法的有效性。在这个项目中，PI将同时对目标细胞进行光磁刺激，并结合能量收集纳米设备的输送，以创造一种新的治疗方法。从这项研究中获得的知识将直接有助于建立高通量筛选药物或毒理学制剂及其对心血管疾病的影响的可靠平台。此外，社会影响是广泛的，因为这项研究衍生的技术将有助于从药物库中同时释放治疗药物和预防感染分子的组合。在持续的大流行期间或未来类似的情况下，在感染预防与重症监护相结合的情况下，对选定药物进行疗效评估将非常有用。由于其跨学科性质，该项目将涉及来自多个科学和技术领域的学生。我们将招募学生，特别是那些在STEM领域代表性不足的学生，并为他们提供支持，以促进学院的研究和创新文化。参与该项目的学生将接触到广泛的观点和想法，从而促进多样性。内皮细胞的慢性氧化应激暴露导致细胞内能量消耗，从而诱导细胞凋亡，这大大增加了心血管疾病的风险，是一个重大的健康问题。慢性氧化损伤后重建正常内皮功能和诱导细胞生长和增殖的机制是复杂的，目前尚不清楚。了解这些过程对全面控制和治疗涉及内皮细胞损伤的疾病具有重要意义。组合疗法的引入，包括协同光磁刺激和多功能纳米级能量收集装置，这些装置具有生物相容性，远程可调，能够按需释放特定药物或药物组合到目标细胞，可以彻底改变涉及内皮损伤疾病的治疗结果。本研究通过实施迄今尚未探索的创新多模式综合策略-混合光磁刺激-将重点放在协同调节细胞内通路以恢复氧化应激诱导后内皮的稳态功能。在这个项目中，主要目标将是：(a)采用分子级能量收集装置来提供光磁和化学线索；(b)确定复合光磁疗能否恢复氧化应激诱导后内皮细胞的稳态功能；(c)探索光磁联合疗法逆转内皮损伤的细胞和分子机制。光磁响应纳米器件将被封装在热激活的聚乙二醇生物聚合物网络中，该网络无毒且具有抗免疫原性。能量收集装置将通过衍生聚合物外壳与特定的质膜受体的配体来靶向细胞。当将细胞结合的纳米器件置于混合光磁激发暴露中时，将执行小分子的控制释放，激活导致内皮损伤修复的信号转导途径，并将激发能转化为化学势，用于三磷酸腺苷合成。此外，混合光磁激励策略将允许在照射过程中使用较弱的交流电磁场与光刺激相结合，从而消除了仅使用交流电磁场辅助疗法的安全问题。将纳米器件和化学线索结合光磁激发策略用于内皮损伤修复的独特方法将刺激多个技术领域，包括心血管疾病监测、药物或毒理学试剂的高通量筛选以及内皮损伤的潜在影响识别。这个项目的主要教育效益将是东南密苏里州立大学学生的互动和直接参与。教育和推广活动包括培训学生使用先进的仪器和开展交叉课程，包括高级本科生和研究生。此外，该项目的研究和教育活动将与东南大学罗纳德·f·麦克奈尔（Ronald F. McNair）目前的本科教育工作相结合，该计划旨在促进STEM领域代表性不足的学生成员的研究经验。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。

Endothelial cells, which line the walls of the blood vessels, are subject to significant stress in a variety of conditions, including diabetes and various inflammatory diseases. This condition massively increases risk for cardiovascular diseases associated with high rates of morbidity and mortality. Current noninvasive approaches lack effective and targeted damage repair. Light therapy, when administered through a particular radiation mode, can extract significant advantages, and thus, is often considered a noninvasive therapeutic approach in regenerative medicine. Nanostructures made from materials with magnetic properties are attractive possibilities for designing novel platforms for similar applications. Thus, it may be possible to enhance the effectiveness of these approaches by aptly combining the optical and the magnetic excitation for tissue repair. In this project, the PI will use simultaneous optical-magnetic stimulation to the targeted cells in combination with the delivery of energy-harvesting nanodevices to create a novel therapeutic approach. The knowledge derived from this research will directly contribute towards reliable platforms for high-throughput screening of pharmaceutical or toxicological agents and their effects on cardiovascular diseases. Additionally, the societal impacts are broad since this research derived technique will be useful to release a combination of therapeutic agents plus infection preventing molecules simultaneously from a drug reservoir. In the middle of an ongoing pandemic or in future situations like this, where infection prevention is of supreme importance in conjunction with the critical care, this will be extremely useful to conduct efficacy assessment on selected drugs. The project, due to its inter-disciplinary nature, will involve students from multiple fields of science and technology. Students, especially those under-represented within STEM fields, will be recruited, and supported to boost the research and innovation culture of the institution. The students involved in the project will be exposed to a wide range of perspectives and ideas, thus fostering diversity. Chronic oxidative stress exposure of the endothelium leading to depletion of intracellular energy and, therefore, induction of apoptosis, which massively increases the risk for cardiovascular diseases, is a significant health problem. Mechanisms to re-establish normal endothelium functioning and induce cell growth and proliferation following chronic oxidative damage are complex and still not well understood. The understanding of these processes is important towards comprehensive control to treat the diseases that involve endothelium damage. Introduction of combinatorial therapeutics consisting of synergistic photo-magnetic stimulation, and multifunctional nanoscale energy-harvesting devices that are biocompatible, remotely tunable, and capable of performing on-demand release of a specific drug or a combination of drugs to the targeted cells can revolutionize the treatment outcomes for diseases that involve endothelium damage. This research, by implementing an innovative multimodal comprehensive strategy that has been unexplored thus far – hybrid photo-magnetic stimulation – will focus on synergistically modulating the intracellular pathways to restore homeostatic functioning of the endothelium following the induction of oxidative stress. In this project, the primary objectives will be: (a) Introduce molecular level energy-harvesting devices to provide photo-magnetic and chemical cues; (b) Determine whether the combinatorial photo-magnetic therapy can restore homeostatic functioning of the endothelium following induction of oxidative stress; and (c) Explore the cellular and molecular mechanism(s) by which the photo-magnetic combinatorial therapeutics would reverse the endothelium damage. Opto-magnetically responsive nanodevices will be encapsulated within a thermo-activated poly(ethylene glycol) based biopolymer network, which is non-toxic, and anti-immunogenic. The energy-harvesting devices will be targeted to cells by derivatizing the polymer shell with ligands for specific plasma membrane receptors. The cell-bound nanodevices, when placed inside the hybrid photo-magnetic excitation exposure, will perform the controlled release of small molecules that activate signal transduction pathways leading to endothelium damage repair, and convert the excitation energy to chemical potential for Adenosine triphosphate synthesis. Additionally, the hybrid photo-magnetic excitation strategy will permit the use of a less intense alternating current magnetic field in combination with optical stimulation during the irradiation process, thus removing the safety concerns associated with using only alternating current magnetic field assisted therapies. A unique approach of nanodevice and chemical cues integration with an opto-magnetic excitation strategy for endothelium damage repair will stimulate several technical fields, including cardiovascular disease monitoring, high-throughput screening of pharmaceutical or toxicological agents, and identification of potential effects on endothelium damage. The primary educational benefit of this project will be the interactions and direct participation of students at Southeast Missouri State University. Educational and outreach activities include training students in advanced instrumentation and conducting cross-listed courses, involving upper-level undergraduate and graduate students. In addition, research and educational activities of the project will be integrated with the current undergraduate educational efforts of the Ronald F. McNair post-baccalaureate achievement initiative at Southeast, which promotes research experiences among members of students under-represented in STEM fields.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.