Notochordal Cell Derived Therapies for Painful Disc Degeneration

脊索细胞衍生疗法治疗疼痛性椎间盘退变

• 批准号: 8599568
• 负责人: James C. Iatridis
• 金额: $ 50.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8599568
• 关键词: Absence of pain sensation; Acute; Address; Adult; Age; Anabolism; Analgesics; Animals; Attention; Back Pain; Bioreactors; Blood Vessels; Cell Adhesion; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cells; Cellular Morphology; Chondroitin Sulfate Proteoglycan; Clinical; Collagen; Conditioned Culture Media; Cues; Custom; Development; Developmental Biology; Disease; Endothelial Cells; Erinaceidae; Exhibits; Gait; Gene Proteins; Genes; Glucose; Goals; Growth; Histology; Human; Hyperalgesia; Hypoxia; In Situ; In Vitro; Inflammatory; Injection of therapeutic agent; Intervertebral disc structure; Investigation; Literature; Low Back Pain; Measurement; Measures; Mechanical Stimulation; Medical; Metabolism; Methods; Modeling; Motor Skills; Neurons; Nociception; Notch Signaling Pathway; Organ Culture Techniques; Outcome; Pain; Pathogenesis; Pathway interactions; Pattern; Phenotype; Production; Proteins; Proteoglycan; Proteomics; Rattus; Recovery; Research; Research Personnel; Research Priority; SHH gene; Safety; Semaphorin-3A; Series; Spinal; Stem cells; Structure; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Time; age related; clinically significant; cost; cytokine; cytotoxic; cytotoxicity; design; economic impact; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; intervertebral disk degeneration; migration; minimally invasive; neurite growth; novel; novel therapeutics; nucleus pulposus; pain inhibition; prevent; protein expression; public health relevance; regenerative; relating to nervous system; repaired; restoration; screening; spine bone structure; therapy design; tissue culture

DESCRIPTION (provided by applicant): Intervertebral disc (IVD) degeneration is a debilitating disorder implicated in the pathogenesis of low back pain with associated medical costs that can exceed $100 billion annually. The overall goal of the proposed research is to introduce novel therapeutic agents and strategies for use in a minimally invasive manner to limit degeneration, restore IVD structure, and reduce painful conditions of degenerative disc disease. Current therapies fail to integrate both structural repair and analgesia. Further, several analgesics are cytotoxic so that developing new therapeutic agents and strategies are a major research priority. The large vacuolated notochordal cells (NCs) in developing animals orchestrate patterning of the IVDs, vertebrae and surrounding spinal structures. Humans and other species that do not retain NCs into adulthood exhibit age related IVD degeneration and researchers have long sought to answer why NCs are lost in humans at young ages. The literature now indicates NCs are progenitor cells and suggests their early disappearance in humans is associated with their differentiation to small chondrocytic nucleus pulposus cells (SNPCs). For the first time, we have a bioreactor and culture methods capable of differentiating NCs into SNPCs so that we can derive therapies from NCs and explore mechanisms for their differentiation. The proposed studies provide a new paradigm for designing an integrated therapeutic intervention derived from trophic agents secreted by NCs to create structure and symptom modifying therapies capable of restoring IVD function and preventing discogenic pain by inhibition of neurovascular growth into the IVD. Aim 1 will determine microenvironment conditions capable of retaining NC phenotype, characterize the phenotypic stability of important genes and proteins of bioactive molecules produced by NCs, and isolate pathways involved in NC differentiation. Aim 2 is a series of descriptive and mechanistic studies that assess therapeutic potential of proteins secreted by NCs with dependent variables that focus on pain inhibition by limiting neurovascular invasion and promoting structural restoration. Aim 3 evaluates designed 'cocktail' treatments for their effects promoting anabolism and inhibiting discogenic pain or predictors of pain in human ex vivo organ culture models and rat in vivo discogenic pain models. This project is significant because of the translational potential to the highly clinically significant problem of discogenic back pain. The approach is innovative because it investigates factors important in developmental biology and introduces them for therapeutic effect using descriptive and mechanistic studies. We focus on therapeutic potential with mechanistic testing and screening studies using novel human organ culture and rat discogenic pain models. Innovation and significance are also high because determining optimal microenvironmental culturing conditions of NCs will help accelerate the growing body of research on these underexplored cells.

描述（由申请人提供）：椎间盘 (IVD) 退变是一种使人衰弱的疾病，与腰痛的发病机制有关，每年相关的医疗费用可能超过 1000 亿美元。拟议研究的总体目标是引入新的治疗药物和策略，以微创方式使用，以限制退变、恢复 IVD 结构并减少退行性椎间盘疾病的痛苦状况。目前的疗法未能整合结构修复和镇痛。此外，一些镇痛药具有细胞毒性，因此开发新的治疗剂和策略是主要的研究重点。发育中动物体内的大型空泡脊索细胞 (NC) 协调 IVD、椎骨和周围脊柱结构的模式。人类和其他在成年后不保留 NC 的物种会表现出与年龄相关的 IVD 退化，研究人员长期以来一直在寻找答案，解释为什么人类在年轻时会丢失 NC。现在的文献表明 NC 是祖细胞，并表明它们在人类中的早期消失与它们分化为小软骨细胞髓核细胞 (SNPC) 有关。我们首次拥有能够将 NC 分化为 SNPC 的生物反应器和培养方法，以便我们可以从 NC 中衍生治疗方法并探索其分化机制。拟议的研究为设计源自 NC 分泌的营养剂的综合治疗干预提供了新的范例，以创建能够恢复 IVD 功能并通过抑制神经血管生长到 IVD 来预防椎间盘源性疼痛的结构和症状修饰疗法。目标 1 将确定能够保留 NC 表型的微环境条件，表征 NC 产生的生物活性分子的重要基因和蛋白质的表型稳定性，并分离参与 NC 分化的途径。目标 2 是一系列描述性和机制研究，评估 NC 分泌的蛋白质的治疗潜力，其因变量侧重于通过限制神经血管侵袭和促进结构恢复来抑制疼痛。目标 3 评估设计的“鸡尾酒”治疗在人类离体器官培养模型和大鼠体内椎间盘源性疼痛模型中促进合成代谢和抑制椎间盘源性疼痛或疼痛预测因子的效果。该项目意义重大，因为它具有解决椎间盘源性背痛这一具有高度临床意义的问题的潜力。该方法具有创新性，因为它研究了发育生物学中的重要因素，并通过描述性和机制研究将它们引入治疗效果。我们专注于使用新型人体器官培养和大鼠椎间盘源性疼痛模型进行机械测试和筛选研究的治疗潜力。创新性和重要性也很高，因为确定 NC 的最佳微环境培养条件将有助于加速对这些尚未开发的细胞的研究。