Programmed cells for targeted articular regenerative medicine

用于靶向关节再生医学的编程细胞

• 批准号: 10442611
• 负责人: Jonathan Matthew Brunger
• 金额: $ 20.35万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442611
• 关键词: Affect; American; Anti-Inflammatory Agents; Antibodies; Arthritis; Behavior; Binding; Biochemical; Biological; Bioluminescence; Cartilage; Cartilage Matrix; Catabolism; Cell Therapy; Cell Transplantation; Cells; Chondrogenesis; Chronic; Clinical; Collagen; Collagen Type II; Cues; Custom; Degenerative polyarthritis; Deterioration; Diagnostic; Disease; Drug Delivery Systems; Engineering; Environment; Epitopes; Family suidae; Feedback; Foundations; Gene Delivery; Gene Expression Profiling; Genetic Engineering; Genetic Transcription; Goals; Health; Histology; Homeostasis; Human; Immobilization; Immunohistochemistry; Inflammation; Injury; Joints; Knee; Lesion; Licensing; Ligands; Limb structure; Localized Disease; Luciferases; Measures; Mechanics; Mediating; Mesenchymal Stem Cells; Methods; Modeling; Monitor; Musculoskeletal; Natural regeneration; Operative Surgical Procedures; Outcome; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Pluripotent Stem Cells; Regenerative Medicine; Regenerative engineering; Reporter; Signal Transduction; Site; Specificity; Synovial Membrane; Synthetic Genes; System; Testing; Therapeutic; Time; Tissues; Transgenes; Transplantation; Work; antagonist; arthropathies; articular cartilage; base; cartilage degradation; cartilage repair; cell behavior; cellular engineering; chemokine; combat; cytokine; delivery vehicle; disability; experimental study; improved; in vitro Model; in vivo; in vivo Model; innovation; joint destruction; joint inflammation; joint injury; mouse model; notch protein; programs; receptor; regeneration function; regenerative; response; spatiotemporal; stem cell differentiation; stem cells; synthetic biology; therapeutic transgene; tool; transgene delivery; transgene expression

PROJECT SUMMARY Osteoarthritis (OA) affects over 32 million Americans and is a leading cause of years lost to disability worldwide. OA is characterized by the breakdown of the collagen II-rich matrix of articular cartilage, as well as inflammation of joint tissues such as the synovium. No disease-modifying drugs exist to treat arthritis, leaving surgery as the eventual result for patients with progressive OA. While existing surgical options offer some clinical benefit, outcomes decline over time due to the inability of these approaches to induce robust, sustained regeneration of joint tissues. Cell engineering strategies have been developed to overcome the limitations of surgical treatments. These strategies deploy cells or gene delivery vehicles to supply anabolic and/or anti-inflammatory factors to the joint; however, these rely on unregulated or only generically controlled expression of transgenes that may negatively impact health when expressed for long durations or outside of pathologic target tissues. Here, we propose to leverage synthetic biology tools to confine expression of transgenes to sites characterized by joint degeneration. Our approach builds on our use of a customized cell sense and response platform in regenerative engineering. This artificial cell signaling system enables us to program cells to react to selected features of a microenvironment by implementing defined transcriptional programs. Our prior studies have illustrated that exposed collagen II serves as a diagnostic hallmark of OA. This proposal capitalizes on our recent demonstration that the synthetic receptor platform selectively licenses cells to detect type II collagen and then upregulate expression of chosen transgenes. The overall goal of our work is to establish synthetic receptor-controlled cells as agents to orchestrate cartilage repair and combat the inflammation associated with joint trauma or chronic joint inflammation. This project will characterize the ability of our receptors to drive stem cells to mediate cartilage repair in an in vitro model of arthropathy (Aim 1) and will assess the ability of transplanted synNotch-programmed cells to detect and respond to cartilage degeneration in an in vivo model of post-traumatic OA (Aim 2).

项目概要 骨关节炎 (OA) 影响着超过 3200 万美国人，是全世界因残疾而损失生命的主要原因。 OA 的特点是富含 II 型胶原蛋白的关节软骨基质的破坏以及炎症 关节组织，如滑膜。目前尚无治疗关节炎的疾病缓解药物，只能通过手术来治疗 进行性骨关节炎患者的最终结果。虽然现有的手术选择提供了一些临床益处， 由于这些方法无法诱导强健、持续的再生，结果随着时间的推移而下降。 关节组织。细胞工程策略已经被开发出来以克服手术治疗的局限性。 这些策略部署细胞或基因传递载体，向细胞提供合成代谢和/或抗炎因子。 联合的;然而，这些依赖于不受监管或仅受一般控制的转基因表达，这些表达可能 当长时间表达或在病理靶组织之外表达时，会对健康产生负面影响。在这里，我们 提议利用合成生物学工具将转基因的表达限制在具有联合特征的位点 退化。我们的方法建立在我们在再生中使用定制的细胞感知和响应平台的基础上 工程。这种人工细胞信号系统使我们能够对细胞进行编程，使其对特定的细胞特征做出反应。 通过实施定义的转录程序来形成微环境。我们之前的研究表明 暴露的 II 型胶原蛋白是 OA 的诊断标志。该提案利用了我们最近的演示 合成受体平台选择性地许可细胞检测 II 型胶原蛋白，然后上调 所选转基因的表达。我们工作的总体目标是建立合成受体控制的细胞 作为协调软骨修复和对抗与关节创伤或慢性相关炎症的药物 关节炎症。该项目将表征我们的受体驱动干细胞介导软骨的能力 在关节病体外模型中进行修复（目标 1），并将评估移植的 synNotch 编程的能力 细胞在创伤后 OA 体内模型中检测软骨退化并做出反应（目标 2）。