Induced pluripotent stem cell therapy for degenerated IVD

诱导多能干细胞治疗退化性 IVD

• 批准号: 9891953
• 负责人: Dmitriy Sheyn
• 金额: $ 11.91万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891953
• 关键词: Acute; Address; Adult; Animal Model; Antiinflammatory Effect; Area; Attenuated; Back Pain; Biology; Bone Tissue; Cartilage; Cell Survival; Cell Therapy; Cells; Child; Chronic; Cicatrix; Data; Development; Disease; Dyes; Educational workshop; Embryonic Development; Environment; Family suidae; Fibrosis; Funding; Gene Delivery; Gene Expression; Gene Expression Profiling; Genetic; Goals; Harvest; Histologic; Human; IL8 gene; Image; Imaging technology; Immunoassay; Immunology; Inflammation; Inflammatory; Injections; Injury; Institute of Medicine (U.S.); Interferon Type II; Interleukin-1 beta; Interleukin-17; Interleukin-6; Intervertebral disc structure; Knowledge; Label; Leadership; Link; Magnetic Resonance Imaging; Measures; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Modeling; Molecular Biology; Monitor; Musculoskeletal; Natural regeneration; Needles; Organ Culture Techniques; Outcome Study; Pain; Parents; Pathogenesis; Patients; Peptides; Phenotype; Physiological; Play; Population; Positioning Attribute; Process; Proteins; Publications; Puncture procedure; Quantitative Reverse Transcriptase PCR; Regenerative Medicine; Rejuvenation; Reporting; Research; Research Personnel; Role; Seasons; Solid; Source; Supervision; Symptoms; TNF gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissue Engineering; Training; Training Programs; Vertebral column; Visit; age related; alternative treatment; base; career; cell type; cytokine; design; disc regeneration; experience; hands on research; immunoregulation; improved; in vivo; in vivo Model; induced pluripotent stem cell; innovation; intervertebral disk degeneration; notochord; novel; nucleus pulposus; preclinical study; quantitative imaging; soft tissue; stem cell therapy; stem cells; targeted treatment; tissue regeneration; transcriptome sequencing

Project Summary/abstract As many as 80% of the adult population experience back pain at some point in their lifetimes. Previous studies have indicated a link between back pain and intervertebral disc (IVD) degeneration in 40% of patients. Despite decades of research, robust therapies targeting underlying causes rather than symptoms are still in the earliest stages of development. Thus, there is an urgent need for alternative treatment, such as stem cell therapy, focused on correcting the underlying pathogenesis of DDD. Dr. Sheyn’s goal is to develop his academic career in musculoskeletal tissue engineering and stem cell therapy field, focusing on spine therapeutics. He has received excellent training in stem cell manipulation and gene delivery, in vivo models, bone tissue engineering and molecular biology. He has established solid track record of publications in the field and demonstrated strong capacity to conduct innovative research. The proposed training program is designed to build on Dr. Sheyn’s background and strengthen his expertise in specific areas most relevant to IVD therapeutics. Under the leadership and sponsorship of Dr. Clive Svendsen, the director of the Cedars-Sinai Regenerative Medicine Institute, Dr. Sheyn will gain experience in the three research areas: 1) development of soft tissue and cartilage biology; 2) immunology and inflammation; 3) quantitative imaging of soft tissue using magnetic resonance imaging (MRI). We will utilize formal workshops and courses and hands-on research supervised by seasoned mentors with extensive track record in these areas and mentorship to achieve those training goals. In the proposed study we will study the link between the possible mechanism of disc degeneration and the potential cell therapy. Firstly, we will investigate the developmental phenotype of novel induced pluripotent stem cell- derived notochordal cells as a potential source of cells to reverse the degeneration process and fibrosis of the disc. This aim will be conducted under mentorship of Dr. Lyons, well-established developmental and musculoskeletal biologist from UCLA and Dr. Hoyland, world expert in the notochord and IVD biology from Manchester U, UK. Secondly we will use the annular injury model of disc degeneration in pigs to study the role of pro-inflammatory and catabolic cytokines expressed by the NP cells under mentorship of Dr. Arditi, world known expert in immunology, inflammation and fibrosis., In Aim 3, the IVD degeneration will be assessed using MRI as shown in preliminary results, but also we will monitor the regeneration of the IVD using iPS-derived notochordal-like cells will be monitored under supervision of Dr. Li, world leader in MR research and imaging. Overall this study will improve our understanding of the disc degeneration and possible regeneration strategies, as well as will serve as excellent vehicle for Dr. Sheyn to strengthen his expertise in areas critical for addressing the DDD therapy and will place him in strong position to establish independent research to compete for substantial funding (R01).

项目摘要/摘要 多达80％的成人人群在一生中的某个时刻经历了背痛。先前的研究 已经表明40％的患者背痛与椎间盘（IVD）变性之间有联系。尽管 数十年的研究，针对潜在原因而不是症状的强大疗法仍在 发展阶段。那迫切需要替代治疗，例如干细胞疗法， 专注于纠正DDD的潜在发病机理。 Sheyn博士的目标是发展他的学术生涯 在肌肉骨骼组织工程和干细胞疗法领域，重点是脊柱治疗。他有 接受了干细胞操纵和基因输送的出色培训，体内模型，骨组织工程 和分子生物学。他已经在该领域建立了稳固的出版物记录，并证明了 强大的进行创新研究的能力。拟议的培训计划旨在基于博士。 Sheyn的背景并加强了他在与IVD疗法最相关的特定领域的专业知识。在下面 Cedars-Sinai再生医学主任Clive Svendsen博士的领导和赞助 研究所，Sheyn博士将在这三个研究领域获得经验：1）软组织和软骨的发展 生物学; 2）免疫学和炎症； 3）使用磁共振对软组织进行定量成像 成像（MRI）。我们将利用经验丰富的正式讲习班，课程和动手研究 在这些领域和指导中具有广泛记录的指导者，以实现这些培训目标。在 拟议的研究我们将研究椎间盘变性机理与电势之间的联系 细胞疗法。首先，我们将研究新型诱导多能干细胞的发育表型 衍生的脊索细胞是扭转变性过程和纤维化的潜在细胞来源 光盘。这个目标将在Lyons博士的心态下进行，并已建立的发展和 UCLA的肌肉骨骼生物学家和Hoyland博士，Notochord和IVD生物学的世界专家 英国曼彻斯特U。其次，我们将使用猪中的椎间盘变性的环形损伤模型来研究角色 NP细胞在Arditi博士的心态下表达的促炎和分解代谢细胞因子，世界 免疫学，感染和纤维化的已知实验。在AIM 3中，将使用IVD变性进行评估 MRI如初步结果所示，但我们也将使用IPS衍生的IVD监测IVD的再生 在MR研究和成像的世界领导者Li博士的监督下，将对脊索状细胞进行监测。 总体而言，这项研究将提高我们对椎间盘退化和可能再生的理解 策略，并将成为Sheyn博士在关键领域增强其专业知识的绝佳工具 解决DDD疗法的问题，并将他处于强大的位置，以建立独立研究 争夺大量资金（R01）。