Polymeric Nanomaterials for Probing and Modulating Innate Immune Responses

文摘:

Abstract: Inflammation is a defense mechanism triggered by innate immune system against any foreign invasion to restore homeostasis, but when it sustains for a prolonged period of several months to years, it transforms into a chronic condition resulting in several harmful diseases. The inflammasome is a hetero-multimeric protein complex known for activating inflammatory caspases followed by subsequent processing of cytokines, which makes it one of the key players during inflammation. Abnormal activation of inflammasomes can initiate undesirable inflammatory responses associated with the progression of chronic inflammatory diseases. Several studies have investigated nanomaterial interactions with immune cells to understand their role in various biological applications and tailor them to different needs. Indeed, several types of nanomaterials have been widely explored to target the immune cells at the disease site to modulate the immune responses. However, our recent studies and several recent reports suggest that many of these nanomaterials activate inflammasomes in immune cells non-specifically, potentially exacerbating the disease. But the comprehensive characterization of the nanomaterial-immune cell interactions that results in inflammasome activation and the unwanted innate immune response is poorly studied due to a lack of appropriate investigative tools. The overall vision of my research program is to design immunoengineering platforms bridging nanoscience and engineering design with manipulation of the immune system to address fundamental and translational questions in immunology. We focus on developing effective immunotherapy strategies by understanding the interactions between different immune system components, between various nanomaterials and immune cells. Specifically, we aim to address fundamental questions in inflammasome biology and how nanomaterial properties affect their interactions with innate immune cells and inflammasome activation. To accomplish this, we propose to engineer a library of multiparametric polymeric nanomaterial platform with various surface and core characteristics in a single system. This will allow us to test the effect of these nanomaterial properties on inflammasome activation, tweaking one property at a time to develop nanomaterial structure-property-function relationships. We have developed novel high-throughput imaging platform to enable monitoring of inflammasome activation in real time. We have also engineered novel imaging probes to monitor inflammasome activation in vivo in real time. Using these tools, over next five years, we aim to understand the interactions between nanomaterials (polymer-based) and immune cells (macrophages, monocytes, dendritic cells and neutrophils) in the context of inflammasome activation and uncover the mechanisms of this activation in vitro and in vivo. In summary, the information obtained from these studies could provide design criteria that guide the development of next-generation of nanomaterials to control, prevent or mitigate inflammasome signaling pathways and also provide a predictive framework for modulation of the inflammasome activation for potential applications in diagnostics and therapy.