BRIGE: Engineering Cytokine Scavenging Nanoparticles for Immunomodulation

1032413Champion 身体的炎症反应是伤口愈合过程中的关键步骤，不仅可以预防感染，还可以提供新组织形成所需的一些信号。然而，在战场上以及医院烧伤和创伤科中看到的大而严重的伤口通常表现出长期的炎症期和明显的疤痕形成。疤痕组织可能非常紧绷和厚重，以至于无法移动，并且需要痛苦的物理治疗或手术干预。有明确的证据表明炎症在疤痕形成中起着重要作用，这表明在愈合过程中控制炎症可以增加功能组织与疤痕组织的比例。这提供了在分子水平上设计能够主动改变炎症环境的材料的机会。称为细胞因子的蛋白质是炎症的重要组成部分，它们指导细胞活动。为了预防感染过程中的炎症，一些病毒和细菌病原体已经进化出结合或降解特定炎症细胞因子的蛋白质，例如肿瘤坏死因子α（TNF-β）。该提案的目标是通过设计清除细胞因子的蛋白质纳米颗粒来模拟这些病原体机制，以实现对炎症的控制，从而应用于严重伤口愈合。智力优点：拟议的工作将评估工程病原体模拟蛋白纳米颗粒调节炎症的能力。目的是（1）设计和制造由病毒TNF-β结合蛋白、可溶性受体和细菌TNF-β降解蛋白酶制成的纳米颗粒； (2)评估纳米粒子对TNF-α的结合或降解能力作为粒子特性的函数； (3)评价纳米颗粒对TNF-α调节的体外细胞反应。这项工作的结果将确立使用活性蛋白质作为治疗材料构建模块的可行性，这是理想的，因为可以操纵它们以提供生物相互作用以及所需的化学和物理性质。这里描述的颗粒不遵循传统的药物输送方法，而是展示出在不直接与细胞相互作用的情况下发挥治疗效果的能力。该提案引入了一类新型抗炎疗法，利用致病病毒和细菌的策略并重新设计它们，以达到治愈患者的最终目标。更广泛的影响：许多患有各种炎症性疾病的人将受益于该提案中生产的新型细胞因子调节材料。然而，这一提议的收获将远远超出预期的科学结果。 PI 计划了各种活动来招募和留住化学工程领域的女性和代表性不足的少数族裔。在最基本的层面上，该提案将为一名代表性不足的研究生和本科生提供支持，保持她当前实验室的多样性。她将提供个人指导，鼓励他们继续从事工程职业，并成为下一代的榜样。 PI 将在夏季 STEPS 项目中服务，招募历史黑人学院的科学/数学专业学生，获得佐治亚理工学院的工程学双学位。她将向项目参与者教授化学工程入门知识，并让一名学生在她的实验室中根据该提案进行研究。该 PI 还积极参与女性工程学 (WIE) 计划，并将参加外展计划，以激发亚特兰大地区初中和高中女生对工程学的兴趣。她还将非正式地指导 WIE 化学工程研究生女性小组。最后，这项工作和文献中的相关例子将被纳入 PI 教授的核心化学工程课程中，将研究与基本工程概念联系起来。

1032413Champion The body's inflammatory response is a critical step in the wound healing process, not only in preventing infection but also in providing some of the signals required for new tissue formation. However, large and severe wounds seen on the battlefield and in the burn and trauma units of hospitals often exhibit a prolonged inflammatory period and significant scar formation. The scar tissue can be so taut and thick that movement is prohibited and painful physical therapy or surgical intervention is required. There is clear evidence that inflammation plays a major role in scar formation, suggesting that control of inflammation during healing can increase the ratio of functional tissue to scar tissue. This presents an opportunity to engineer, at the molecular level, materials that actively change the inflammatory environment. Proteins called cytokines are a critical component of inflammation and they direct cellular activities. To prevent inflammation during infection, some viral and bacterial pathogens have evolved proteins that bind or degrade specific inflammatory cytokines, such as tumor necrosis factor alpha (TNF-£\). The goal of this proposal is to mimic these pathogen mechanisms by engineering protein nanoparticles that scavenge cytokines to achieve control over inflammation for applications in severe wound healing. Intellectual Merit: The proposed work will assess the ability of engineered pathogen-mimetic protein nanoparticle to modulate inflammation. Objectives are to (1) design and fabricate nanoparticles made from viral TNF-£\ binding proteins, soluble receptors and bacterial TNF-£\ -ndegrading proteases; (2) assess nanoparticle binding or degrading capacities for TNF-£\ as a function of particle properties; (3) evaluate the in vitro cellular response to TNF-£\ modulation by nanoparticles. The results of this work will establish the feasibility of using active proteins as therapeutic material building blocks which is desirable because they can be manipulated to provide both biological interactions as well as required chemical and physical properties. The particles described here do not follow a traditional drug delivery approach but instead will demonstrate the ability to exert a therapeutic effect without interacting directly with cells. This proposal introduces a new class of anti-inflammatory therapeutics, harnessing the strategies of pathogenic viruses and bacteria and re-engineering them for the ultimate goal of healing patients. Broader impacts: Many people, with a variety of inflammatory conditions, would benefit from the novel cytokine modulating materials produced in this proposal. However, this proposal will have gains well beyond the anticipated scientific results. The PI has planned a variety of activities to recruit and retain women and under-represented minorities in chemical engineering. At the most basic level this proposal will support one graduate and undergraduate under-represented students, maintaining the diversity of her current lab. She will provide individual mentoring to encourage them to continue their careers in engineering and serve as role models for the next generation. The PI will serve in the summer STEPS program to recruit science/math majors at Historically Black Colleges for a dual degree in engineering at Georgia Tech. She will teach introductory chemical engineering to program participants and have one student perform research from this proposal in her lab. The PI is also active in the Women in Engineering (WIE) program and will participate in outreach programs to generate excitement for engineering in Atlanta-area middle and high school girls. She will also informally mentor the WIE chemical engineering graduate women's group. Finally, this work and related examples from the literature will be incorporated into core chemical engineering courses taught by the PI, relating research to fundamental engineering concepts.