Friday, May 9, 2025
5/9/2025
Endogenous Protease Mediated Delivery of Engineered Immunomodulatory Extracellular Vesicles - PROJECT SUMMARY/ABSTRACT This application proposes a tailored research training plan that is designed to promote my development into an independent clinician-scientist. The plan includes a rigorous laboratory training experience in multiple techniques as well as a customized professional and career development plan. Furthermore, the training plan is supported by outstanding institutional resources, including a strong and interwoven research community and a supportive mentorship team. My research area of interest is translationally-relevant biomimetic approaches to tissue repair. In the field of tissue engineering, there is a need for therapeutic tools that target specific inflammatory and regenerative pathways. The NLRP3 inflammasome pathway is activated in several systemic diseases, such as type I and type II diabetes. This pathway also contributes to chronic inflammation and directly impairs repair and regeneration of various tissues within the body including bone and craniofacial tissues. Diabetes-related chronic inflammation and poor craniofacial bone repair are significant oral healthcare problems. Mesenchymal stem cell-derived extracellular vesicles (MSC EVs) and their miRNA cargo have high therapeutic potential for immunomodulation in dental diseases and craniofacial tissue regeneration. Several miRNAs within MSC EV cargo have been identified to regulate and suppress the NLRP3 pathway. However, there is a gap in knowledge regarding the lack of mechanistic approaches to direct pathway-specific manipulation of inflammation using EVs and to achieve controlled release of EVs to employ their therapeutic effects. The proposed research will address this gap in knowledge through developing a controlled release system for engineered anti-inflammatory EVs at wound sites. This release system will use an alginate-based hydrogel platform to deliver engineered EVs. The alginate-based hydrogel can be functionally modified by incorporating cell/EV binding motifs to the alginate backbone. The results of this proposal will work towards the long-term goal of maximizing the therapeutic potential of EVs and enhancing tissue repair. Aim 1 will utilize miRNA-based EV engineering to generate engineered MSC EVs to target the NLRP3 inflammasome pathway using miRNA-22-3p as the candidate. Aim 2 entails developing a photocrosslinkable hydrogel for the controlled release of engineered EVs using tissue resident metalloproteases abundant at wound sites as a trigger for EV release. Aim 3 is focused on assessing the efficacy of the engineered EVs and the delivery system in vivo using a diabetic mouse calvarial defect model. Overall, successful completion of these aims will provide me with a comprehensive training in EV biology and related techniques, stem cell biology, molecular biology, immunology, biomaterial design, imaging, animal handling and related histology and immunohistochemical techniques. Results from this work will directly address oral healthcare issues such as diabetes-related chronic inflammation and poor craniofacial bone repair.
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