Induced pluripotent stem cell therapy for degenerated IVD

项目摘要/摘要 多达80%的成年人口在一生中的某个时候经历过背部疼痛。以前的研究 在40%的患者中，有研究表明背痛与椎间盘退变之间存在联系。尽管 几十年的研究，针对潜在原因而不是症状的强有力的治疗仍处于最早阶段 发展的各个阶段。因此，迫切需要替代疗法，如干细胞疗法， 重点纠正了DDD的潜在发病机制。施恩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治疗领域，专注于脊柱治疗。他有 在干细胞操作和基因传递、活体模型、骨组织工程方面接受过出色的培训 和分子生物学。他在该领域建立了坚实的出版物记录，并展示了 较强的创新研究能力。拟议的培训计划旨在建立在Dr。 并加强他在与IVD治疗学最相关的特定领域的专业知识。在……下面 雪松-西奈再生医学中心主任克莱夫·斯文森博士的领导和赞助 施恩博士将在以下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)利用磁共振对软组织进行定量成像 成像(MRI)。我们将利用由经验丰富的人监督的正式研讨会和课程以及实践研究 在这些领域拥有广泛跟踪记录的导师，并为实现这些培训目标提供指导。在 建议的研究我们将研究椎间盘退变的可能机制和潜在的 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-- 来源的脊索细胞作为一种潜在的细胞来源来逆转兔的退变过程和纤维化 光盘。这一目标将在莱昂斯博士的指导下进行，他是一位久负盛名的发展和 加州大学洛杉矶分校的肌肉骨骼生物学家和霍兰德博士，来自加州大学洛杉矶分校的脊索和IVD生物学的世界专家 英国曼彻斯特大学。其次，我们将利用猪椎间盘退变的环状损伤模型来研究其作用。 在Arditi博士的指导下，NP细胞表达的促炎和分解代谢细胞因子 已知的免疫学、炎症和纤维化专家。在目标3中，将使用以下方法评估IVD变性 MRI显示的初步结果，但我们也将监测再生的IVD使用iPS来源 脊索样细胞将在李博士的监督下进行监测，李博士是磁共振研究和成像的世界领先者。 总体而言，这项研究将提高我们对椎间盘退变和可能的再生的理解 战略，并将成为Sheyn博士加强其在关键领域的专业知识的极佳工具 解决DDD疗法，并将使他处于强有力的地位，建立独立的研究 争夺大量资金(R01)。

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).