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: 8687598
• 负责人: James C. Iatridis
• 金额: $ 46.3万
• 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/8687598
• 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）变性是一种使人衰弱的疾病，涉及下背痛的发病机理，相关的医疗费用每年可能超过1000亿美元。拟议研究的总体目标是以微创方式引入新颖的治疗剂和策略，以限制退化，恢复IVD结构并减少退化性椎间盘疾病的痛苦条件。当前的疗法无法整合结构修复和镇痛。此外，几种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。发育中的动物中的大型空白蛇形细胞（NC）策划了IVD，椎骨和周围脊柱结构的图案。人类和其他不保留NC的物种进入成年后表现出与年龄相关的IVD变性，研究人员长期以来一直在试图回答为什么年轻人在人类中丧失的NCS。文献现在表明NC是祖细胞，表明它们在人类中的早期消失与它们与小软骨细胞核细胞（SNPC）的分化有关。我们第一次有一种生物反应器和培养方法，能够将NC区分开为SNPC，因此我们可以从NCS中得出疗法并探索其分化的机制。拟议的研究提供了一种新的范式，用于设计由NCS分泌的营养剂衍生的综合治疗干预措施，以创建结构和症状，以修饰能够恢复IVD功能的疗法，并通过抑制IVD中的神经血管生长来预防丝鼻疼痛。 AIM 1将确定能够保留NC表型的微环境条件，表征NC产生的重要基因和蛋白质的表型稳定性，以及与NC分化有关的分离途径。 AIM 2是一系列描述性和机械研究，它们评估了NCS分泌的蛋白质的治疗潜力，这些蛋白质具有因变量而分泌的，这些变量通过限制神经血管入侵并促进结构恢复，以侧重于疼痛抑制。 AIM 3评估了设计的“鸡尾酒”处理，以促进合成代谢并抑制人体离体器官培养模型中的疼痛和疼痛的预测因素，并在体内粘附疼痛模型中进行大鼠。该项目很重要，因为转化潜力是高度临床上显着的椎间盘基础疼痛问题。该方法具有创新性，因为它研究了在发育生物学中重要的因素，并使用描述性和机械研究将其引入治疗效果。我们专注于使用新型的人体器官培养和大鼠二聚体疼痛模型的机械测试和筛查研究的治疗潜力。创新和意义也很高，因为确定NCS的最佳微环境培养条件将有助于加速对这些未经置换的细胞的研究体系。