BRIGE: Engineering Cytokine Scavenging Nanoparticles for Immunomodulation

BRIGE：用于免疫调节的工程细胞因子清除纳米颗粒

• 批准号: 1032413
• 负责人: Julie Champion
• 金额: $ 17.5万
• 依托单位: Georgia Tech Research Corporation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1032413&HistoricalAwards=false
• 关键词: BRIGE; Engineering; Cytokine; Scavenging; Nanoparticles

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.

1032413冠军身体的炎症反应是伤口愈合过程中的关键步骤，不仅在预防感染，而且在提供新组织形成所需的一些信号。然而，在战场上和医院的烧伤和创伤科看到的大而严重的伤口通常表现出延长的炎症期和显著的疤痕形成。疤痕组织可以是如此紧张和厚，运动是禁止和痛苦的物理治疗或手术干预是必要的。有明确的证据表明，炎症在瘢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瘢痕组织的比例。这为在分子水平上设计积极改变炎症环境的材料提供了机会。被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。为了防止感染期间的炎症，一些病毒和细菌病原体已经进化出结合或降解特定炎性细胞因子（例如肿瘤坏死因子α（TNF-α））的蛋白质。该提案的目标是通过工程化蛋白质纳米颗粒来模拟这些病原体机制，所述蛋白质纳米颗粒抑制细胞因子以实现对炎症的控制，用于严重伤口愈合。智力优势：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 1结合蛋白、可溶性受体和细菌TNF-β 1降解蛋白酶制成的纳米颗粒;（2）评估纳米颗粒结合或降解TNF-β 1的能力作为颗粒性质的函数;（3）评估纳米颗粒对TNF-β 1调节的体外细胞应答。这项工作的结果将建立使用活性蛋白质作为治疗材料构建块的可行性，这是理想的，因为它们可以被操纵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递送方法，而是将展示在不直接与细胞相互作用的情况下发挥治疗效果的能力。该提案介绍了一类新的抗炎疗法，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：许多人，与各种炎症条件下，将受益于新的细胞因子调节材料在此提议中产生。然而，这一提议的收获将远远超出预期的科学成果。PI计划了各种活动，以招募和留住化学工程领域的妇女和代表性不足的少数民族。在最基本的层面上，这项建议将支持一个研究生和本科生代表性不足的学生，保持她目前的实验室的多样性。她将提供个人指导，鼓励他们继续他们的工程职业生涯，并为下一代的榜样。PI将在夏季STEPS项目中任职，在历史上的黑人学院招收科学/数学专业的学生，获得格鲁吉亚理工学院的工程双学位。她将教授课程参与者介绍化学工程，并让一名学生在她的实验室中执行该提案的研究。PI还积极参与妇女在工程（WIE）计划，并将参加外展计划，以产生兴奋的工程在亚特兰大地区的初中和高中女生。她还将非正式地指导WIE化学工程研究生妇女团体。最后，这项工作和相关的文献中的例子将被纳入PI教授的核心化学工程课程，将研究与基本工程概念联系起来。