CAREER: Engineering Polymeric Nanomaterials for Programming Innate Immunity

从癌症到糖尿病，再到慢性感染，免疫系统在几乎每一种疾病中都扮演着重要的角色。因此，利用免疫系统的力量和特异性具有巨大的--而且在很大程度上仍未被开发--改善人类健康和福祉的潜力。然而，对于能够对产生预期结果所必需的正确类型的免疫反应进行精确和可预测的“编程”的技术的需求仍然没有得到满足。这一职业奖的目标是开发新的合成材料，用于“编码”免疫信息，并严格控制它们向免疫系统的器官、细胞和途径的传递。在这个项目中，PI将设计出模拟病原体的聚合物纳米颗粒，用于连接多个免疫线索，并控制它们传递到免疫细胞的适当途径。这项研究将解决对控制、理解和利用免疫系统的新工具的基本需求，免疫系统在疫苗开发、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将开发一个教育推广计划，创建动手、基于探究的课程，以促进贫困学生在STEM领域的积极参与，同时提高对疫苗、免疫系统和跨学科科学的重要性的认识。先天免疫系统的细胞使用模式识别受体(PRRs)感知入侵的病原体或病理组织，这些受体定位于细胞表面、内体隔室和细胞质中。这些通路之间存在显著的串扰，从这些受体发出的信号的整合触发并塑造了免疫反应的表型和大小。因此，调节免疫信号的传递到细胞内的多个受体是控制免疫的基础。然而，目前还缺乏合成工具来正确编码这些物理化学上不同的线索，以提供所需的免疫学结果。这一职业奖的目标是设计一个通用的基于纳米颗粒的平台，用于严格调控先天免疫传感通路的分子定义激活剂的传递。总体假设是，具有精确可调的pH响应和内体不稳定活性的聚合物囊泡(即聚合体)将能够协调传递触发表面、内体和胞质PRR的多个明确的信号。将检验这一假设，并通过以下特定目标实现目标：1)设计具有精确可调pH响应拆解、释放和内吞体失稳特性的多聚体；2)研究多聚体性质对单独或联合给药的PRR激动剂活性的影响；3)证明负载多个PRR激动剂的聚合体可用于编程免疫反应的幅度和表型。这项拟议的研究将导致以下有影响力的科学和技术成果：1)开发将扩大免疫调节的可药物靶标的材料；2)关于如何设计材料以协调来自细胞内不同受体的信号事件的基础知识；以及3)阐明可用于增强和塑造疫苗免疫反应的PRR之间新的依赖于材料的协同作用。通过将新的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内具有智力价值。为了增强该职业奖的更广泛的影响，将开发一个综合研究、教育和推广计划，以1)培训高中生、本科生和研究生进行生物工程研究；2)为初中和高中课堂创建并广泛传播动手的、基于探究的教育科学课程；3)促进未被充分代表和/或处于不利地位的初中生和高中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卫生保健重大挑战方面的重要性的认识。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”倡议，为纳什维尔公立学校和田纳西州农村社区的初中生和高中生开发一种廉价的、动手操作的移动教学套件。

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.