CAREER: Engineering Polymeric Nanomaterials for Programming Innate Immunity

职业：工程聚合物纳米材料用于编程先天免疫

• 批准号: 1554623
• 负责人: John Wilson
• 金额: $ 50万
• 依托单位: Vanderbilt University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1554623&HistoricalAwards=false
• 关键词: CAREER; Engineering; Polymeric; Nanomaterials; Programming

1554623Wilson, John T. From cancer, to diabetes, to chronic infections, the immune system plays an important role in nearly every disease. Accordingly, harnessing the power and specificity of the immune system has enormous - and still largely untapped - potential to improve human health and wellbeing. However, there remains an unmet need for technologies that enable precise and predictable "programming" of the correct type of immune response necessary to yield a desired outcome. The goal of this CAREER Award is to develop new synthetic materials for "encoding" immunological messages and tightly regulating their delivery to the organs, cells, and pathways of the immune system. In this project, the PI will engineer pathogen-mimicking polymer nanoparticles for connecting multiple immunological cues and controlling their delivery to the appropriate pathways of immune cells. This research will address a fundamental need for new tools to control, understand, and harness the immune system, which has significant ramifications in vaccine development, cancer immunotherapy, and treatment of autoimmune disorders. Additionally, the PI will develop an educational outreach program that creates hands-on, inquiry-based lessons to catalyze active engagement in STEM areas by underprivileged students, while increasing awareness about vaccines, the immune system, and the importance of interdisciplinary science. Cells of the innate immune system sense invading pathogens or pathologic tissue using pattern recognition receptors (PRRs) that are localized on the cell surface, in endosomal compartments, and in the cytosol. There is significant crosstalk between these pathways, and the integration of signals emanating from these receptors triggers and shapes the phenotype and magnitude of an immune response. Therefore, regulating the delivery of immunologic cues to multiple receptors localized throughout a cell is fundamental to controlling immunity. Yet, there is a lack of synthetic tools that can properly encode these physicochemically diverse cues to confer a desired immunological outcome.The objective of this CAREER Award is to engineer a versatile nanoparticle-based platform for tightly regulating the delivery of molecularly defined activators of innate immune sensing pathways. The overall hypothesis is that polymer vesicles (i.e., polymersomes) engineered with precisely tunable pH-responsive and endosome-destabilizing activity will enable the coordinated delivery of multiple defined cues that trigger surface, endosomal, and cytosolic PRRs. The hypothesis will be tested and the objectives accomplished through the following specific aims: 1) engineer polymersomes with precisely tunable pH-responsive disassembly, release, and endosome destabilizing properties; 2) investigate the effect of polymersome properties on the activity of PRR agonists delivered alone or in combination; 3) demonstrate that polymersomes loaded with multiple PRR agonists can be used to program the magnitude and phenotype of an immune response. The proposed research will lead to the following impactful scientific and technological outcomes: 1) the development of materials that will expand the repertoire of druggable targets for immunomodulation; 2) fundamental knowledge of how materials can be designed to coordinate signaling events originating from diverse receptors localized throughout the cell; and 3) elucidation of new material-dependent synergies between PRRs that can be exploited to enhance and shape immune responses to vaccines. By integrating the synthesis of novel and rationally designed materials with fundamental studies elucidating new structure-activity relationships, the proposed research will have intellectual merit within the biomaterials, biopharmaceutical, and immunology communities.To enhance the broader impacts of this CAREER Award, an integrated research, education, and outreach program will be developed to 1) train high school, undergraduate, and graduate students in bioengineering research; 2) create and broadly disseminate hands-on, inquiry-based educational science lessons for middle and high school classrooms; 3) catalyze active and authentic engagement in STEM subjects by underrepresented and/or underprivileged middle and high school students; 4) increase awareness about vaccines, the immune system, and the importance of interdisciplinary teams in solving grand challenges in health care. In collaboration with the School for Science and Math at Vanderbilt (SSMV) and the Vanderbilt Student Volunteers for Science (VSVS), a 'students teaching students' initiative will be launched to develop an inexpensive, hands-on, mobile lesson kit for middle and high school students in Nashville public schools and rural Tennessee communities.

1554623威尔逊，约翰T. 从癌症到糖尿病，再到慢性感染，免疫系统在几乎所有疾病中都起着重要作用。因此，利用免疫系统的力量和特异性在改善人类健康和福祉方面具有巨大的潜力，而且在很大程度上尚未开发。 然而，对于能够精确和可预测地“编程”产生期望结果所必需的正确类型的免疫应答的技术，仍然存在未满足的需求。该职业奖的目标是开发新的合成材料，用于“编码”免疫信息并严格调节其向免疫系统的器官，细胞和途径的传递。在这个项目中，PI将设计模拟病原体的聚合物纳米颗粒，用于连接多种免疫学信号并控制它们传递到免疫细胞的适当途径。这项研究将解决对新工具的基本需求，以控制，理解和利用免疫系统，这在疫苗开发，癌症免疫治疗和自身免疫性疾病的治疗中具有重大影响。此外，PI将制定一项教育推广计划，创建实践，基于探究的课程，以促进贫困学生积极参与STEM领域，同时提高对疫苗，免疫系统和跨学科科学重要性的认识。先天免疫系统的细胞使用位于细胞表面、内体区室和胞质溶胶中的模式识别受体（PRR）来感测入侵的病原体或病理组织。在这些途径之间存在显著的串扰，并且从这些受体发出的信号的整合触发并塑造免疫应答的表型和幅度。因此，调节免疫信号向位于整个细胞中的多个受体的传递是控制免疫的基础。然而，目前还缺乏合成工具，可以适当地编码这些物理化学上不同的线索，赋予所需的免疫学outgoal.The目标的CAREER奖是设计一个多功能的纳米粒子为基础的平台，用于严格调节先天免疫传感途径的分子定义的激活剂的交付。总体假设是聚合物囊泡（即，用精确可调的pH响应性和内体去稳定化活性工程化的聚合物囊泡（例如聚合物囊泡）将使得能够协调递送触发表面、内体和胞质PRR的多种限定的线索。将通过以下具体目标来测试该假设并实现目标：1）工程化具有精确可调的pH响应性分解、释放和内体去稳定化性质的聚合物囊泡; 2）研究聚合物囊泡性质对单独或组合递送的PRR激动剂的活性的影响; 3）证明负载有多种PRR激动剂的聚合物囊泡可用于编程免疫应答的幅度和表型。拟议的研究将导致以下有影响力的科学和技术成果：1）材料的开发，将扩大免疫调节的药物靶标库; 2）如何设计材料以协调源自整个细胞中不同受体的信号传导事件的基础知识;和3）阐明PRR之间的新材料依赖性协同作用，其可用于增强和形成对疫苗的免疫应答。通过将新型和合理设计的材料的合成与阐明新的结构-活性关系的基础研究相结合，拟议的研究将在生物材料，生物制药和免疫学社区中具有智力价值。为了提高这个职业奖的更广泛影响，将开发一个综合研究，教育和推广计划，以1）培训高中，本科，2）为初中和高中课堂创建并广泛传播实践，基于探究的教育科学课程; 3）促进代表性不足和/或贫困的初中和高中学生积极和真实地参与STEM学科; 4）提高对疫苗，免疫系统以及跨学科团队在解决医疗保健重大挑战中的重要性的认识。与范德比尔特科学与数学学院（SSMV）和范德比尔特学生科学志愿者（VSVS）合作，将发起一项“学生教学生”的倡议，为纳什维尔公立学校和田纳西州农村社区的中学生开发一个便宜的、动手的、移动的课程包。