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.

摘要该申请是针对PA-20-272（NOT-TR-21-028）提交的。骨关节炎（OA）是关节炎的最普遍形式。许多药物在人类临床的各个阶段失败由于治疗结果不良或临床前发育过程中未发现的意外毒性而引起的试验表明可用模型的缺陷用于开发疾病改良药物。体外模型尚未完全涵盖了OA是“全联合疾病”的概念。动物模型具有固有的缺陷，因为人类的生理/基因组差异。该预测促使OA药物的范式转移发展。最近，在父母赠款（UG3/uh3tr002136）的支持下，我们的团队设计了一个体外微生物生理关节芯片（微连接），整合骨软骨，滑膜和脂肪类似物使用人间充质干细胞（MSC）。通过将白介素1β（IL-1β）引入培养基仅喂养滑膜组织，“发炎的滑膜组织”诱导的软骨降解已经是成功地在微连接中建模。验证微连接作为模型以预测新颖的效率在人类中对OA的治疗干预措施，评估具有证明有效性的代理商的影响至关重要 OA在微连接中。目前，我们已经测试了Naproxen，Wnt途径抑制剂SM04690和Sclerostin，成纤维细胞生长因子18，白介素-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3的组织抑制剂，卡尔生素，环胺，辛伐他汀，罗格列酮和核因子（NF）-κB诱饵寡脱氧核苷酸。另外，我们将使用微连接来评估MSC衍生产品的治疗价值，包括MSC条件培养基和/或MSC衍生的外泌体。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，该数据缺乏自主组织和分析结果。因此，在这个新项目中，我们建议使用微生物生理系统数据库（MPS-DB）团队可以从药物测试中存储和处理我们的数据。具体来说，我们将上传实时PCR 来自药物测试的Luminex分析数据进入MPS-DB。通过内置工具，我们将能够快速分析数据并通过系统地评估药物测试中的最佳治疗候选者整个数据。拟议的工作对于验证对骨关节炎和建模的微连接很重要微连接预测人类药物反应的效用。从研究中的公开访问数据使用微连接也将对从事传统OA模型（例如体外细胞）的研究人员很有价值文化和动物模型。例如，微连接中确定的生物标志物将告知特定分子专注于使用传统模型在研究中进行的研究。最后，这些上传向MPS-DB的研究数据还清楚地告知利益相关者有关测定，模型，细胞来源和响应的信息为了使化合物加速将微连接转换为临床应用。

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.