Reprogramming redox-controlled innate and adaptive immune responses by antioxidant polymer microvesicles

通过抗氧化剂聚合物微泡重新编程氧化还原控制的先天和适应性免疫反应

• 批准号: 2208831
• 负责人: Richard Dluhy
• 金额: $ 62.37万
• 依托单位: University of Alabama at Birmingham
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2208831&HistoricalAwards=false
• 关键词: Reprogramming; redox; controlled; innate; adaptive

NON-TECHNICAL SUMMARY This award by the Biomaterials program in the Division of Materials Research to the University of Alabama at Birmingham (UAB) is to develop vesicular biomaterials as an antioxidant therapy for the treatment of diabetes. Type 1 diabetes (T1D) is an autoimmune disease resulting in oxidative stress, inflammation, and pancreatic beta-cell destruction. Current antioxidant therapies are hindered by limitations of antioxidant effectiveness, including low ability to target reactive oxygen species (ROS) sites (e.g. mitochondria) and selectivity for immune cells. The proposed research develops a new class of nanostructured antioxidant vesicular biomaterials that promote our understanding of immune regulation in T1D. This vesicular platform can be adapted for enhanced functionalities, providing transformative knowledge for developing antioxidant materials for the treatment of a broad spectrum of immune-mediated disorders. The benefits to the biomaterials community are a better understanding of antioxidant material properties for immune suppression. Scientific problems that can be addressed by the knowledge obtained in this project may also include understanding the immune responses in T1D. The educational objective of the project is to expand a discovery-driven multidisciplinary biomaterials science program at UAB and to promote diversity from high school, undergraduate-, graduate-, and post-graduate levels. Students and scholars will be trained in materials and immunological aspects of biomaterials science and will participate in intensive, multidisciplinary collaborations. The collaborative efforts will expand interdisciplinary research and provide awareness of the biomedical research community at UAB toward a need for antioxidant polymer-based biomaterials. The educational and outreach activities of this project will enhance science, technology, engineering, and mathematics (STEM) participation of women and underrepresented minorities and STEM education, increase public awareness and engagement with science through knowledge dissemination, and increase partnerships with industry to increase economic competitiveness in the USA.TECHNICAL SUMMARY The goal of this project is to develop a microvesicular biomaterial, giant unilamellar vesicles (GUVs), with controlled antioxidant activity and to determine the physicochemical and antioxidant effects of these microvesicles on innate and adaptive immune responses to restore immune tolerance in T1D. The GUVs will be designed through self-assemblies of degradable amphiphilic triblock copolymers with antioxidants integrated within the vesicle interior, while antigens anchored to the vesicle outer surface will promote antigen presentation by antigen-presenting cells (APCs) to target autoreactive T cells. The specific aims of the proposed study are as follows: (1) Synthesize GUVs modified with T1D autoantigens and study the microvesicle uptake by APCs. (2) Investigate the effects of antioxidant microvesicles on ROS synthesis and redox-dependent signaling pathways in APCs. (3) Determine the effects of antioxidant microvesicles on polarization of macrophage and dendritic cells and the activation of autoreactive T cells. The complementary studies outlined in our proposal will test hypotheses that effective control of redox signaling pathways and, subsequently, decreasing innate and adaptive immune responses can be achieved by rationally designing antioxidant GUVs. The specific impact of the proposed study is in: (a) developing a series of synthetic routes to new types of antioxidant polymer self-assembled vesicles; (b) bringing knowledge on the effects of GUV structure and antioxidant type on the GUV antioxidant activity; (c) understanding the impact of microvesicle size, rigidity, and antigen-modification on interactions with immune cells; (d) obtaining fundamental insights into the selective APC targeting with antigen mirovesicles to regulate proinflammatory responses of innate and adaptive immune cells; and (e) understating the role of antioxidant GUVs on modulation of redox-regulated pathways involved in immune cell activation and proinflammatory chemokine/cytokine synthesis. Our results will impact the development of polymer self-assembled vesicles with a broad range of antioxidant activity and will provide a fundamental understanding of materials' physical, chemical, and immunomodulatory properties.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.

该奖项由阿拉巴马大学伯明翰分校（UAB）材料研究部生物材料项目颁发，旨在开发用于治疗糖尿病的囊泡生物材料抗氧化疗法。1型糖尿病（T1D）是一种自身免疫性疾病，导致氧化应激、炎症和胰腺β细胞破坏。目前的抗氧化疗法受到抗氧化效果的限制，包括靶向活性氧（ROS）位点（如线粒体）的能力低和对免疫细胞的选择性低。本研究开发了一类新的纳米结构抗氧化囊泡生物材料，促进了我们对T1D免疫调节的理解。这种囊泡平台可用于增强功能，为开发抗氧化材料提供变革性知识，用于治疗广谱免疫介导的疾病。对生物材料界的好处是更好地了解抗氧化材料的免疫抑制特性。通过本项目获得的知识可以解决的科学问题还可能包括了解T1D的免疫反应。该项目的教育目标是在UAB扩展发现驱动的多学科生物材料科学课程，并促进高中，本科，研究生和研究生水平的多样性。学生和学者将在生物材料科学的材料和免疫学方面接受培训，并将参与密集的多学科合作。此次合作将扩大跨学科研究，并提高UAB生物医学研究界对抗氧化聚合物生物材料需求的认识。该项目的教育和推广活动将加强妇女和代表性不足的少数民族对科学、技术、工程和数学（STEM）的参与，以及STEM教育，通过知识传播提高公众对科学的认识和参与，并加强与工业界的伙伴关系，以提高美国的经济竞争力。本项目的目标是开发一种具有可控抗氧化活性的微泡生物材料，巨型单层囊泡（GUVs），并确定这些微泡对先天和适应性免疫反应的理化和抗氧化作用，以恢复T1D的免疫耐受。guv将通过可降解的两亲性三嵌段共聚物的自组装来设计，抗氧化剂整合在囊泡内部，而抗原固定在囊泡外表面，将促进抗原呈递细胞（APCs）的抗原呈递到靶向自身反应性T细胞。本研究的具体目的如下：(1)合成以T1D自身抗原修饰的guv，并研究apc对其微泡的摄取。(2)研究抗氧化微泡对APCs中ROS合成及氧化还原依赖信号通路的影响。(3)测定抗氧化微泡对巨噬细胞和树突状细胞极化及自身反应性T细胞活化的影响。在我们的建议中概述的补充研究将测试假设，有效控制氧化还原信号通路，随后减少先天和适应性免疫反应可以通过合理设计抗氧化guv来实现。所提出的研究的具体影响在于：(a)开发了一系列合成新型抗氧化聚合物自组装囊泡的途径；(b)引入有关GUV结构和抗氧化剂类型对GUV抗氧化活性影响的知识；(c)了解微泡大小、硬度和抗原修饰对与免疫细胞相互作用的影响；(d)获得选择性APC靶向抗原微泡调控先天和适应性免疫细胞的促炎反应的基本见解；(e)低估了抗氧化guv在免疫细胞活化和促炎趋化因子/细胞因子合成中氧化还原调控通路的调节作用。我们的研究结果将影响具有广泛抗氧化活性的聚合物自组装囊泡的发展，并将提供对材料的物理，化学和免疫调节特性的基本理解。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。