Cartilage response to compression injury: A platform for therapeutics discovery

说明： 该项目寻求在理解和发现用于治疗软骨创伤的新的治疗剂方面迅速推进最先进的技术。过重的负荷和钝力创伤是导致软骨病理和最终“修复不足”的关节表面逐渐恶化和功能衰竭的原因。事实上，局灶性软骨缺陷患者的生活质量评分与严重骨关节炎(OA)患者相当，进一步强调了早期干预的必要性。创伤后骨性关节炎(PTOA)是指关节创伤后直接出现软骨病变的骨性关节炎患者亚群，实际上可能始于关节的创伤性损伤。PTOA在普通人群和军人人群中都很普遍，在目前的临床实践中很大程度上是无法治疗和无法治疗的。这种损伤后软骨修复的挑战是天然组织固有的较差的愈合能力，以及在损伤时缺乏可用于保持细胞活性、生物合成活性和促进内部修复的分子。此外，目前还没有高通量的筛选方法来模拟这种损伤状态，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疗法。我们的设计平台是以软骨样组织的微观和大量发展为中心的。然后，我们机械地冲击这些软骨组织类似物(CTA)，并评估它们的细胞和整体退变反应，作为侮辱后时间的函数。在这项建议的目标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，并针对损伤后软骨中的退化信号开发快速和具有成本效益的结果指标，从而使测试平台适用于高 吞吐量筛选(HTS)。在目标2中，我们将结合工程CTA和天然组织来验证这一新型设备，以便匹配损伤后发生的关键信号事件的时间和幅度。在目标3中，我们将使用这个经过验证的系统来筛选商业上可用的小分子文库，以识别在软骨细胞对损伤的反应中重要的分子。在目标4中，我们将使用可溶和生物材料介导的传递系统来测试已识别的化合物(及其组合)在人体组织类似物和天然人类软骨对损伤的反应中的治疗效果。这些给药系统旨在实现快速转化为后续的临床前动物模型，并最终转化为人类临床试验。这项研究具有很高的翻译性，因为它涉及钝器创伤和软骨损伤的常见情况，这种情况在现役军人中非常普遍，并将为这一临床领域的小分子发现提供一个新的和迫切需要的测试平台。

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.