Developing the common marmoset as a translational model of age-related osteoarthritis

考虑到年龄增长是原发或自然发生的骨关节炎(OA)的最高风险因素， 未得到满足的需求是，在当前的OA模型中，衰老本身并没有得到很好的研究。因此，导致这种现象的机制 年龄相关性骨性关节炎的发病和早期进展尚不完全清楚，疾病调整疗法 都不存在。因此，发布NOT-AG-19-037的目的是为了加速描述新的或未充分利用的特性 模型“和”测试假说，将导致更好地理解启动和 办公自动化的进展。非人灵长类动物是进化上与人类最接近的近亲，它们有许多共同之处 人类衰老的生理生物学特征。常见的绒猴是最小的类人猿 具有很高的人类翻译潜力和适合研究启动机制的寿命的灵长类 与年龄相关的疾病。在年轻的雄性啮齿动物中，mTOR活性增加有助于骨性关节炎和 抑制mTOR可防止损伤诱导的骨性关节炎。然而，目前尚不清楚mTOR抑制是否可以延缓 在老年人中普遍存在的自然发生的骨性关节炎的发病机制。此外，目前还不清楚mTOR是否 与男性一样，在女性中也参与了骨性关节炎的发病。为了解决这些知识上的差距，这项提议 将追求两个具体目标。在目标1中，我们测试了年龄对绒猴自然发生的骨性关节炎的影响。为 为此，我们将使用圣安东尼奥·内森休克中心的绒猴样本来综合评估 高分辨率微型计算机在关节软骨、软骨下骨、滑膜和半月板中的应用 成年、老年和老年恒河猴队列中的断层扫描、组织病理学和免疫组织化学。我们会 还要评估OA是否伴随着与疼痛、静止和死亡有关的绒猴行为和活动。 在目标2中，我们将检验雷帕霉素抑制mTOR将降低自然发生的膝骨性关节炎的假设 雄性和雌性绒猴的疼痛相关的病理和改变行为。为此，我们将利用 一项正在进行的用安慰剂或mTOR抑制剂雷帕霉素治疗的恒河猴寿命研究。样品将会是 在尸检中收集，以评估关节软骨，软骨下骨， 滑膜和半月板。MTOR抑制将通过测量下游蛋白质和基因靶标进行评估 通过IHC和RNA测序。这个项目完成后，我们预计将把绒猴发展为 一种新的自然发生的年龄相关性骨性关节炎的翻译模型，我们将确定mTOR和 下游通路有助于自然发生的骨性关节炎的病因和治疗。建立 绒猴作为识别可利用机制的模型，反过来将有助于促进疾病的发展-- 修改人类骨性关节炎的治疗方法。

Considering that increasing age is a top risk factor for primary, or naturally occurring osteoarthritis (OA), an unmet need is that aging per se is not well studied in current OA models. Therefore, the mechanisms that cause the onset and early progression of age-related OA are incompletely understood and disease modifying therapies do not exist. Therefore, NOT-AG-19-037 was issued to “accelerate the characterization of new or underutilized models” and “test hypotheses that will lead to an improved understanding of the mechanisms of initiation and progression of OA.” Non-human primates are the closest evolutionary relative to humans and share many physiological and biological characteristics of human aging. The common marmoset is the smallest anthropoid primate with high potential for human translation and a lifespan amenable to studying mechanisms that initiate age-related disease. In young, male rodents, increased mTOR activity contributes to the onset of OA and inhibition of mTOR prevents injury-induced OA. However, it is not yet known if mTOR inhibition could slow the pathogenesis of naturally occurring OA that is prevalent in aging humans. Further, it is unknown if mTOR contributes to the pathogenesis of OA in females like in males. To resolve these gaps in knowledge, this proposal will pursue two specific aims. In Aim 1, we test the effect of age on naturally occurring OA in the marmoset. For this aim, we will use marmoset samples from the San Antonio Nathan Shock Center to comprehensively evaluate OA in articular cartilage, subchondral bone, synovium and menisci by high-resolution micro-computed tomography, histopathology, and immunohistochemistry in cohorts of adult, old, and older marmosets. We will also evaluate if OA is accompanied with marmoset behavior and activity linked to pain, immobility, and mortality. In Aim 2, we will test the hypothesis that mTOR inhibition by rapamycin will lower naturally occurring knee OA pathology and modify behavior linked to pain in both male and female marmosets. For this aim, we will leverage an ongoing lifespan study in marmosets treated with placebo or the mTOR inhibitor rapamycin. Samples will be collected at necropsy to evaluate OA pathology and mTOR inhibition in articular cartilage, subchondral bone, synovium and menisci. mTOR inhibition will be evaluated by measuring downstream protein and gene targets via IHC and RNA sequencing. By completion of this project it is expected that we will develop the marmoset as a novel translational model of naturally occurring age-related OA and that we will identify if mTOR and downstream pathways contribute to the etiology and treatment of naturally occurring OA. Establishing the marmoset as a model to identify exploitable mechanisms will in turn help facilitate the development of disease- modifying therapies for human OA.