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

将微关节模型药物测试生成的数据存入微生理学系统数据库

基本信息

批准号：
10434624
负责人：
Hang Lin
金额：
$ 7.71万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-20 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434624
关键词：
Adipose tissue Administrative Supplement Aftercare Animal Model Animals Arthritis BMP7 gene Biological Biological Assay Biological Markers Biological Models Calcitonin Cartilage Diseases Cell Culture Techniques Cells Clinical Research Clinical Trials Conditioned Culture Media Consumption Data Database Management Systems Degenerative polyarthritis Deposition Disease Disease model Drug Screening Engineering Feeds Future Gene Expression Genes Genomics Health Histology Human In Vitro Interleukin-1 beta Joints Manuals Manuscripts Mesenchymal Stem Cells Methods Modeling Molecular Naproxen Nuclear Pathway interactions Pharmaceutical Preparations Physiological Process Research Research Personnel Simvastatin Source Synovial Fluid Synovial Membrane Synovitis System TIMP3 gene Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect Translations Treatment Efficacy Treatment outcome Work anakinra analog arthropathies base cartilage degradation clinical application clinically relevant collagenase 3 computerized data processing cyclopamine drug candidate drug development drug response prediction drug testing fibroblast growth factor 18 in vitro Model inhibitor/antagonist microphysiology system novel therapeutic intervention osteochondral tissue parent grant preclinical development response rosiglitazone stem cell exosomes tool

项目摘要

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.

摘要本申请是根据 PA-20-272 (NOT-TR-21-028) 提交的。骨关节炎（OA）是最常见的关节炎形式，许多药物在人类临床的各个阶段都失败了。由于治疗结果不佳或临床前开发期间未发现的意外毒性而进行的试验，这表明用于开发疾病缓解药物的现有模型的缺陷并不完全。 OA 是一种“全关节疾病”的概念，因为动物模型具有固有的缺陷。与人类的生理/基因组差异促使 OA 药物发生范式转变。最近，在家长资助（UG3/UH3TR002136）的支持下，我们的团队设计了一个集成骨软骨、滑膜和脂肪类似物的体外微生理关节芯片（microJoint）使用人间充质干细胞 (MSC) 通过将白细胞介素 1 β (IL-1β) 引入培养基中。仅供给滑膜组织，“滑膜组织发炎”引起的软骨退化已被证实在 microJoint 中成功建模验证 microJoint 作为模型预测新颖的功效。对于人类 OA 的治疗干预，评估已证实有效的药物的影响至关重要微关节中的 OA 目前，我们已经测试了萘普生、Wnt 通路抑制剂 SM04690 和硬化蛋白，成纤维细胞生长因子18、白细胞介素1受体拮抗剂我们将继续测试其他提议的药物，包括骨形态发生蛋白7、降钙素、金属蛋白酶组织抑制剂3、Kartogenin、此外，我们还使用环巴明、辛伐他汀、罗格列酮和核因子 (NF)-κB 诱饵寡脱氧核苷酸。将使用 microJoint 评估 MSC 衍生产品的治疗价值，包括 MSC 调理的产品因此，我们期望产生大量的定量数据。目前，我们使用Microsoft Excel来处理所有数据，缺乏自主组织和处理的机制。因此，在这个新项目中，我们建议使用微生理学系统数据库。 (MPS-Db) 团队存储和处理我们的药物测试数据具体来说，我们将上传实时 PCR。通过内置工具，我们将能够快速地将药物测试中的 Luminex 检测数据导入 MPS-Db。通过系统评估所有药物测试来分析数据并确定最佳治疗方案所提出的工作对于验证微关节在骨关节炎建模中的作用很重要。 microJoint 在预测人类药物反应方面的效用该研究使用的公开数据。 microJoint 对于研究传统 OA 模型（例如体外细胞）的研究人员也很有价值例如，微关节中识别的生物标志物将告知具体的情况。分子重点关注使用传统模型进行的研究。 MPS-Db 的研究数据还清楚地告知利益相关者有关测定、模型、细胞来源和测定反应的信息化合物，加速微关节转化为临床应用。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Creation of a Knee Joint-on-a-Chip for Modeling Joint Diseases and Testing Drugs.

DOI：
10.3791/64186
发表时间：
2023-01-27
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Makarcyzk MJ;Li ZA;Yu I;Yagi H;Zhang X;Yocum L;Li E;Fritch MR;Gao Q;Bunnell BA;Goodman SB;Tuan RS;Alexander PG;Lin H
通讯作者：
Lin H

Differences in the intrinsic chondrogenic potential of human mesenchymal stromal cells and iPSC-derived multipotent cells.

DOI：
10.1002/ctm2.1112
发表时间：
2022-12
期刊：
Clinical and translational medicine
影响因子：
10.6
作者：
通讯作者：

Graphene oxide-functionalized nanocomposites promote osteogenesis of human mesenchymal stem cells via enhancement of BMP-SMAD1/5 signaling pathway.

DOI：
10.1016/j.biomaterials.2021.121082
发表时间：
2021-10
期刊：
Biomaterials
影响因子：
14
作者：
Li Z;Xiang S;Lin Z;Li EN;Yagi H;Cao G;Yocum L;Li L;Hao T;Bruce KK;Fritch MR;Hu H;Wang B;Alexander PG;Khor KA;Tuan RS;Lin H
通讯作者：
Lin H

Aberrant Expression of COX-2 and FOXG1 in Infrapatellar Fat Pad-Derived ASCs from Pre-Diabetic Donors.