Depositing Data Generated from Drug Test on microJoint Model into the Microphysiology Systems Database

摘要

ABSTRACTS This application is being submitted in response to PA-20-272 (NOT-TR-21-028). Osteoarthritis (OA) is the most prevalent form of arthritis. Many drugs fail at various stages of human clinical trials due to poor treatment outcomes or unexpected toxicity that were not identified during preclinical development, suggesting deficiencies of available models for developing disease-modifying drugs. In vitro models do not fully encompass the concept that OA is a “whole joint disease”. Animal models have inherent deficiencies because of physiological/genomic differences with humans. This predicament has prompted a paradigm shift in OA drug development. Recently, with the support from the parent grant (UG3/UH3TR002136), our team has engineered an in vitro microphysiological joint chip(microJoint) that integrates the osteochondral, synovial, and adipose analogs using human mesenchymal stem cells (MSCs). Through introducing the interleukin 1 beta (IL-1β) into the medium that feeds the synovium tissue only, "inflamed synovial tissue"-induced cartilage degradation has been successfully modeled in the microJoint. To validate the microJoint as a model to predict the efficacy of novel therapeutic interventions in OA in humans, it is critical to assess the impact of agents with proven efficacy for OA in the microJoint. Currently, we have tested Naproxen, Wnt pathway inhibitors SM04690 and sclerostin, fibroblast growth factor 18, interleukin-1 receptor antagonist. We will continue to test other proposed drugs, including Bone morphogenetic protein 7, calcitonin, Tissue inhibitor of metalloproteinase 3, Kartogenin, cyclopamine, simvastatin, rosiglitazone, and nuclear factor (NF)-κB decoy oligodeoxynucleotide. In addition, we will use the microJoint to assess the therapeutic value of MSC-derived products, including the MSC-conditioned medium, and/or MSC-derived exosomes. Therefore, we expect to generate copious amounts of quantitative data. Currently, we use Microsoft Excel to process all data, which lacks a mechanism to autonomously organize and analyze the results. In this new project, we thus propose to work with the Microphysiology Systems Database (MPS-Db) team to store and process our data from the drug tests. Specifically, we will upload the real-time PCR and Luminex assay data from drug tests into the MPS-Db. Through the built-in tool, we will be able to quickly analyze the data and determine the best treatment candidate from the drug tests by systemically assessing all the data as a whole. The proposed work is important to validating the microJoint in modeling osteoarthritis and the utility of microJoint in predicting drug responses in humans. The publicly accessible data from the study using the microJoint will also be valuable to researchers working on the traditional OA models, such as in vitro cell culture and animal models. For example, the biomarkers identified in the microJoint will inform the specific molecules to focus on the studies conducted in studies using traditional models. Lastly, the uploading of these research data to the MPS-Db also clearly informs stakeholders on assays, models, cell sources, and responses to compounds, accelerating the translation of the microJoint into clinical application.