NSF Award
2208831
NON-TECHNICAL SUMMARY <br/>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.<br/><br/>TECHNICAL SUMMARY <br/>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.<br/><br/>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.
