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: 8926246
• 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/8926246
• 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; 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： 该项目旨在迅速促进艺术的状态，以理解和发现新的治疗剂，以治疗软骨创伤性损伤。过多的负荷和钝力创伤负责发起和促进软骨病理，最终是“修复”的关节表面，逐渐恶化并在功能上失败。实际上，局灶性软骨缺陷的患者具有与严重骨关节炎（OA）相当的生活质量评分，进一步强调了早期干预的需求。创伤后OA（PTOA）定义了OA患者的子集，其软骨病理直接出现是由于关节创伤而出现的，实际上可能是从关节的创伤性损伤开始。 PTOA在一般和军事人群中都是广泛的，并且在当前的临床实践中在很大程度上无法治疗且未治疗。损伤后软骨修复的挑战是天然组织的固有愈合能力固有的较差，并且缺乏在受伤时可以使用的分子来保留细胞生存能力，生物合成活性和促进Intrinsi修复。此外，目前尚无对这种损伤状态建模的高吞吐量筛查方法，因此可以快速鉴定新的治疗剂可以改善临床实践和受伤后的患者结局。我们的设计平台集中在微型尺度和大量的软骨类组织的发展。然后，我们会机械影响这些软骨组织类似物（CTA），并评估其细胞和整体退化反应，这是侮辱后时间的函数。在本提案的目标1中，我们将扩展现有的经过验证的高通量测试系统，以适应更大的样本数量，并制定受伤后软骨中降解信号的快速和成本效益的结果指标，从而使测试平台适合于高 吞吐量筛选（HTS）。在AIM 2中，我们将与工程的CTA和天然组织一起验证这种新型设备，以匹配受伤后发生的关键信号事件的时间和幅度。在AIM 3中，我们将使用此经过验证的系统来筛选市售的小分子库，以确定在软骨细胞对损伤反应中重要的分子。在AIM 4中，我们将同时使用可溶性和生物材料介导的递送系统，以测试已鉴定化合物（及其组合）在人体组织类似物中的治疗疗效和对损伤的天然人软骨反应。 这些递送系统旨在快速转化为随后的临床前动物模型，并最终转换为人类临床试验。这项研究具有很高的转化，因为它与钝力创伤和软骨伤害的所有太混乱实例有关，这种情况在现役军事人群中极为普遍，并且将为该临床领域中的小分子发现提供一个新颖而急需的测试平台。