Cartilage response to compression injury: A platform for therapeutics discovery

软骨对压缩损伤的反应：治疗发现的平台

• 批准号: 8669832
• 负责人: George R. Dodge
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669832
• 关键词: Accidents; Aftercare; Age; Animal Model; Apoptosis; Athletic Injuries; Attenuated; Biochemistry; Biocompatible Materials; Biological Assay; Biomedical Engineering; Cartilage; Cartilage injury; Catabolism; Cell Death; Cell Survival; Cells; Cellular biology; Chondrocytes; Clinical; Clinical Treatment; Clinical Trials; Complement; Coupled; Data; Defect; Degenerative polyarthritis; Development; Devices; Early Intervention; Engineering; Event; Extracellular Matrix; Fostering; Free Radicals; Future; Gene Expression; General Population; Goals; Healed; Health; Human; In Vitro; Individual; Inflammation Mediators; Injury; Interleukin-1; Joint repair; Joints; Libraries; Measures; Mechanics; Mediating; Mediator of activation protein; Membrane; Methods; Military Personnel; Modeling; Nitric Oxide; Orthopedics; Outcome; Outcome Measure; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Population; Process; Production; Published Comment; Quality of life; Route; Rupture; Sampling; Signal Transduction; Signaling Molecule; Simulate; Staging; Stress; Surface; Suspension Culture; System; TNF gene; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Translations; Trauma; Treatment Efficacy; Work; analog; articular cartilage; attenuation; base; biological adaptation to stress; cartilage development; cartilage repair; clinical practice; cost effective; design; healing; high throughput screening; high throughput technology; human tissue; improved; in vivo; inhibitor/antagonist; injured; injury and repair; novel; novel therapeutics; pre-clinical; prototype; public health relevance; repaired; response; response to injury; restorative treatment; scale up; screening; small molecule; small molecule libraries; tool

DESCRIPTION: This project seeks to rapidly advance the state of the art in understanding and discovering new therapeutic agents for the treatment of traumatic injury to cartilage. Excessive loads and blunt force trauma are responsible for initiating and furthering cartilage pathology and eventually an "under repaired" joint surface that progressively deteriorates and functionally fails. Indeed, patients with focal cartilage defects have quality of life scores comparable to those with severe osteoarthritis (OA), further emphasizing the need for early intervention. Post-traumatic OA (PTOA) defines the subset of OA patients whose cartilage pathology emerged directly as a consequence of trauma to the joint and in fact probably started with the traumatic injury to the joint. PTOA is widespread in both the general and military population, and is largely untreatable and untreated in current clinical practice. The challenge in cartilage repair after such injuries i the inherent poor healing capacity of the native tissue and the lack of molecules that can be used at the time of injury to preserve cell viability, biosynthetic activities, and foster intrinsi repair. Moreover, there is currently no high throughput screening method that models this injury state, and so no clear route forward for the rapid identification of novel therapeutics that could improve clinical practice and patient outcomes after injury. Our design platform is centered on the development of cartilage- like tissues on the micro-scale and in large quantities. We then mechanically impact these cartilage tissue analogs (CTAs) and assess their cellular and overall degenerative response as a function of time subsequent to insult. In Aim 1 of this proposal, we will scale up an existing validated high throughput testing system to accommodate even larger sample numbers and develop rapid and cost effective outcome measures specific to degradative signaling in cartilage after injury, thus making the testing platform suitable for high throughput screening (HTS). In Aim 2, we will validate this novel device in conjunction with engineered CTAs and native tissue, so as to match the timing and magnitude of key signaling events that occur after injury. In Aim 3, we will use this validated system to screen commercially available small molecule libraries in order to identify molecules important in chondrocyte response to injury. In Aim 4, we will use both soluble and biomaterial-mediated delivery systems in order to test the therapeutic efficacy of identified compounds (and their combinations) in human tissue analogs and native human cartilage response to injury. These delivery systems are designed to enable rapid translation to subsequent pre-clinical animal models and ultimately to human clinical trials. The study is highly translational in that it relates to the all too commo instance of blunt force trauma and injury to cartilage, a condition extremely prevalent in the active duty military population, and will provide a novel and much needed testing platform for small molecule discovery in this clinical domain.

描述： 该项目旨在快速推进理解和发现用于治疗软骨创伤的新治疗剂的最新技术水平。过度负荷和钝力创伤会引发和加剧软骨病理学，并最终导致“修复不足”的关节表面逐渐恶化和功能失效。事实上，局灶性软骨缺损患者的生活质量评分与严重骨关节炎 (OA) 患者相当，这进一步强调了早期干预的必要性。创伤后 OA (PTOA) 定义了 OA 患者的子集，其软骨病理学直接由于关节创伤而出现，实际上可能始于关节创伤性损伤。 PTOA 在普通人群和军人群体中广泛存在，并且在目前的临床实践中基本上是无法治疗和未经治疗的。此类损伤后软骨修复的挑战在于天然组织固有的较差愈合能力，以及缺乏在损伤时可用于保持细胞活力、生物合成活性和促进内在修复的分子。此外，目前还没有模拟这种损伤状态的高通量筛选方法，因此没有明确的路线来快速识别可以改善临床实践和损伤后患者预后的新型疗法。我们的设计平台以微尺度和大批量的软骨样组织开发为中心。然后，我们对这些软骨组织类似物 (CTA) 进行机械冲击，并评估它们的细胞和整体退行性反应，作为损伤后时间的函数。在本提案的目标 1 中，我们将扩大现有经过验证的高通量测试系统，以容纳更大的样本数量，并开发针对损伤后软骨中的降解信号传导的快速且具有成本效益的结果测量，从而使测试平台适合高通量测试。 通量筛选（HTS）。在目标 2 中，我们将结合工程 CTA 和天然组织来验证这种新型装置，以便匹配受伤后发生的关键信号事件的时间和强度。在目标 3 中，我们将使用这个经过验证的系统来筛选市售小分子文库，以识别在软骨细胞对损伤反应中重要的分子。在目标 4 中，我们将使用可溶性和生物材料介导的递送系统来测试已识别化合物（及其组合）在人体组织类似物中的治疗功效以及天然人类软骨对损伤的反应。 这些输送系统旨在能够快速转化为后续的临床前动物模型，并最终转化为人体临床试验。这项研究具有高度转化性，因为它与钝器外伤和软骨损伤的常见情况有关，这种情况在现役军人中极为普遍，并将为小分子发现提供一个新颖且急需的测试平台。这个临床领域。