Role of the cartilage endplate in spinal disc degeneration

项目摘要 下背痛是残疾的主要原因，与椎间盘退变密切相关。椎间盘营养不良是 是参与变性发作和进展的关键因素，也是可能阻碍 生物疗法的成功。这个新项目的前提是低软骨终板（CEP）渗透性 限制椎间盘营养供应和细胞功能，我们可以识别营养供应充足的患者， 通过非侵入性评估CEP渗透性，可能受益于生物治疗。我们提出 在细胞、组织和人体受试者中进行的创新研究，将：1）确定CEP渗透性的临界值 在静态和动态负荷下营养和代谢物运输所需的; 2）发现组成和 阻碍溶质转运的微观结构特征; 3）验证对 这些特征;和4）确定人受试者中低CEP渗透性的临床相关性。 提出了三个互补的目标。在目标1中，我们将建立CEP之间的定量关系 渗透性、细胞密度和椎间盘细胞功能。通过孵育 通过使用具有宽范围渗透率的尸体CEP样品的腔室，我们将确定 CEP渗透性是维持与健康椎间盘相关的细胞密度所必需的。我们还将量化 动态载荷增强了溶质在CEP上的运移，并发现了CEP渗透率的范围， 溶质大小的传输增强是最大的。在目标2中，我们将确定 溶质运移和CEP生化成分、基质孔隙度和组织的各种测量。这 知识将提供CEP组成和椎间盘健康之间机械联系。在目标3中，我们将测试 使用新的MRI技术组合， 对CEP通透性和椎间盘细胞代谢应激敏感。我们还将比较 CEP渗透性低与血管分布差的贡献。这些研究的结果将解决 未满足的临床需求，并通过以下方式产生广泛影响：1）提供经验证的工具和机制框架， 确定CEP渗透性在椎间盘退变严重程度中的作用; 2）建立第一个非侵入性 选择标准，以确定可以支持生物疗法所需的更高营养需求的椎间盘; 和3）指导通过增强CEP渗透性来改善椎间盘健康的新治疗的开发。

PROJECT SUMMARY Low back pain is the leading cause of disability, and is closely linked to disc degeneration. Poor disc nutrition is a key factor involved in degeneration onset and progression, and is a major obstacle that could hinder the success of biologic therapies. The premise of this new project is that low cartilage endplate (CEP) permeability limits disc nutrient supply and cell function, and that we can identify patients with adequate nutrient supply who might benefit from biologic therapy through non-invasive assessment of CEP permeability. We propose innovative studies in cells, tissues, and human subjects that will: 1) identify critical values of CEP permeability needed for nutrient and metabolite transport under static and dynamic loads; 2) discover compositional and microstructural characteristics that hinder solute transport; 3) validate MRI techniques that are sensitive to these characteristics; and 4) determine the clinical relevance of low CEP permeability in human subjects. Three complementary aims are proposed. In Aim 1 we will develop a quantitative relationship between CEP permeability, cell density, and disc cell function using a novel in vitro diffusion chamber. By incubating the chambers with cadaveric CEP samples with a wide range of permeabilities, we will establish critical values of CEP permeability necessary to sustain cell densities associated with healthy discs. We will also quantify how dynamic loads enhance solute transport across the CEP and discover the range of CEP permeabilities and solute sizes where transport enhancement is greatest. In Aim 2 we will determine the relationship between solute transport and various measures of CEP biochemical composition, matrix porosity, and organization. This knowledge will provide a mechanistic link between CEP composition and disc health. In Aim 3 we will test the clinical relevance of low CEP permeability in human subjects using a combination of new MRI techniques that are sensitive to CEP permeability and disc cell metabolic stress. We will also compare the relative contributions of low CEP permeability vs. poor vascularity. The results from these studies will address an unmet clinical need and exert a broad impact by: 1) providing validated tools and a mechanistic framework to determine the role of CEP permeability in disc degeneration severity; 2) establishing the first non-invasive selection criteria to identify discs that can support the higher nutrient demands required by biologic therapies; and 3) guiding development of new treatments that improve disc health by enhancing CEP permeability.