CAREER: Elucidating structure-function relationships of inflammasome-activating nanomaterials

该奖项全部或部分由《2021年美国救援计划法案》（公法117-2）资助。摘要：该职业奖旨在开发聚合物纳米材料并研究其对免疫细胞功能的影响，特别是炎症小体的激活，炎症小体是一种在正常和病理（导致疾病）过程中控制免疫细胞功能的多蛋白复合物。通过改变聚合物构建块的自组装，所提出的纳米材料集将激活不同的炎性小体功能，并将被用作评估其表面和核心化学模式如何影响免疫细胞的摄取、细胞内命运和炎性小体激活的工具。拟议研究的结果将产生一套新的指导方针，这些指导方针将为设计新型纳米材料提供明确的标准，这些纳米材料可引起可预测程度的炎性体激活，并可用于生物应用，包括免疫治疗和疫苗。该项目的教育目标是将拟议的研究模块整合到为K-12、大学和研究生等不同教育水平的学生开发的几个教育计划中，并增加来自代表性不足群体的学生参与生物工程研究。这些努力包括将指导和研究经验整合到免疫工程和生物工程课程中，为化学工程，生物材料和免疫学新兴界面的多样化劳动力提供独特的学习经验，为来自代表性不足群体的当地K-12学生举办夏季研讨会，为女性和代表性不足的学生提供新的研究经验，以鼓励和促进这些学生参与生物工程领域。从代表性不足的群体中招募研究生，并建立一个对免疫工程感兴趣的教师和学生的在线公开课程网络，以传播、讨论和合作。技术摘要：本职业建议的目标是建立强大和综合的研究和教育计划：(1)提供了对不同纳米材料如何与免疫细胞相互作用导致炎症小体激活的基本理解，(2)推进了炎症小体激活纳米材料在生物应用领域的研究，包括针对炎症性疾病的研究，(3)鼓励和激发了一组不同的K-12学生、本科生和研究生参与学习并为生物工程领域做出贡献。本提案将建立一个具有不同表面和核心性质的聚合超分子纳米粒子库，以阐明纳米材料性质对炎性小体激活的影响，并确定其潜在的分子机制。具体来说，将开发具有可调表面和核心特性的超分子聚合物纳米材料，以确定它们如何影响各种免疫细胞的摄取、细胞内命运和炎性体激活。通过评估溶酶体破坏-组织蛋白酶B成熟和钙流入-线粒体功能障碍途径的关键成分，将剖析炎症小体响应各种纳米材料激活的机制。PI的长期教育目标是指导和培养来自大学预科（K-12），本科和研究生水平的各种学生骨干，使其成为下一代生物工程师，成为能够通过学术，工业或创业途径为社会和不断增长的科学知识做出贡献的批判性思想家。为了实现这一目标，本项目的教育目标包括：(1)将指导和研究经验整合到教育课程中，包括基于项目的工程师生物学课程和基于实验室的免疫工程课程；(2)鼓励和促进来自代表性不足群体的K-12学生参与生物工程领域，利用目前的努力，组织提供实践培训的暑期讲习班，研究生举办“科学日”，其中包括各种活动，如学生演讲、科学知识问答和团队竞赛；(3)设计和开发一个在线资源，用于向教师和研究生共享免疫工程课程材料。(4)提高对工程师如何为生物学和免疫学领域做出贡献的认识，通过将我们的研究成果传播给更广泛的社区，包括研究界和一般人群，来促进人类健康。拟议的研究将产生一套新的指导方针，为设计下一代新型纳米材料的结构和功能需求提供明确的标准，这些纳米材料可引起可预测的炎症小体激活程度，并可用于各种生物应用。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。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).NON-TECHNICAL ABSTRACT:This CAREER award proposes to develop polymeric nanomaterials and investigate their effects on immune cell functions, specifically, activation of the inflammasome, a multiprotein complex that controls immune cell functions during normal and pathological (leading to disease) processes. By varying the self-assembly of their polymeric building blocks, the proposed set of nanomaterials will activate different inflammasome functions, and will be used as tools to evaluate how their surface and core chemical patterns influence uptake, intracellular fate, and inflammasome activation in immune cells. The results from the proposed studies will generate a set of new guidelines that will provide clear criteria for the design of novel nanomaterials that elicit predictable degrees of inflammasome activation and can be used for biological applications, including immunotherapy and vaccines. The project’s educational goals are to integrate the proposed research modules into several educational programs developed for students at various educational levels spanning the K-12, college, and graduate levels and increase the participation of students from underrepresented groups in bioengineering research. These efforts include the integration of mentorship and research experiences into immuno-engineering and bioengineering courses to provide a unique learning experience to a diverse workforce at the emerging interface of chemical engineering, biomaterials, and immunology, a summer workshop for local K-12 students from underrepresented groups, new research experiences for women and underrepresented students to encourage and promote the involvement of these students in the field of bioengineering, recruiting graduate students from underrepresented groups and an online open course network of teachers and students interested in immunoengineering to disseminate, discuss, and collaborate. TECHNICAL ABSTRACT:The goals of this CAREER proposal are to establish strong and integrated research and educational program that: (1) provides a foundational understanding of how different nanomaterials interact with immune cells resulting in inflammasome activation, (2) advances the field of inflammasome-activating nanomaterials for biological applications including targeting inflammatory diseases and (3) encourages and inspires a diverse set of K-12 students, undergraduate and graduate students to participate in learning and contributing to the bioengineering field. This proposal will develop a library of polymeric supramolecular nanoparticles with different surface and core properties to elucidate the effects of nanomaterial properties on inflammasome activation and identify the underlying molecular mechanisms. Specifically, supramolecular polymeric nanomaterials with tunable surface and core properties will be developed to determine how they influence uptake, intracellular fate, and inflammasome activation in various immune cells. The mechanisms underlying inflammasome activation in response to various nanomaterials will be dissected by assessing key components of lysosomal disruption–cathepsin B maturation and calcium influx-mitochondrial dysfunction pathways. The PI’s long-term educational goal is to mentor and train the diverse cadre of students from pre-college (K-12), undergraduate and graduate levels as the next generation of bioengineers to become critical thinkers capable of contributing to society and the growing body of scientific knowledge either through academic, industrial or entrepreneurial route. Towards that goal, the educational aims for this project include: (1) integration of mentorship and research experiences into the educational curriculum, including project-based biology for engineers course and a lab-based immunoengineering course; (2) to encourage and promote the involvement of K-12 students from underrepresented groups in the bioengineering field by leveraging current efforts in organizing summer workshops that provide hands-on training and graduate students run ‘Science Day’ that will include various activities such as students presentations, science trivia and team-based competition; (3) designing and developing an online resource for sharing immunoengineering course materials to instructors and graduate students. (4) to increase awareness about how engineers can contribute to the biology and immunology field to advance human health by disseminating outcomes of our research to broader communities, including the research community and the general population. The proposed research will generate a set of new guidelines that will provide clear criteria for structural and functional requirements to design the next generation of novel nanomaterials that elicit predictable degrees of inflammasome activation and can be used for various biological applications.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.