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

开发普通狨猴作为年龄相关骨关节炎的转化模型

基本信息

批准号：
10348880
负责人：
Adam R Konopka
金额：
$ 19.91万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348880
关键词：
Adult Affect Age Aging Autophagocytosis Autopsy Behavior Biologic Characteristic Biology Biomechanics Callithrix Callithrix jacchus jacchus Cavia Cell Aging Cell Proliferation Cessation of life Clinical Data Degenerative Disorder Degenerative polyarthritis Development Disease Etiology FGFR3 gene FRAP1 gene Female Gene Targeting Haplorhini Health Care Costs Hindlimb Histology Histopathology Human Human Characteristics Immunohistochemistry Impairment Incidence Injury Joints Knee Knee Osteoarthritis Knowledge Link Longevity Measures Mediating Meniscus structure of joint Modeling Nature Pain Pathogenesis Pathology Pathway interactions Peptide Hydrolases Physiological Placebos Primates Proteins Resolution Risk Factors Rodent Role Salmon Sampling Severities Shock Sirolimus Structure Synovial Membrane Testing Time Tissues Translations Weight Woman age effect age related articular cartilage bone cohort disability improved inhibitor/antagonist innovation male microCT mortality mouse model nonhuman primate novel parathyroid hormone-related protein pathogen prevent public health relevance sex subchondral bone transcriptome sequencing translational model

项目摘要

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.

考虑到年龄增长是原发性或自然发生的骨关节炎（OA）的首要风险因素，未满足的需求是，在当前的OA模型中没有很好地研究老化本身。因此，导致年龄相关性OA的发病和早期进展尚不完全清楚，并不存在因此，发布了NOT-AG-19 - 037，以"加速新的或未充分利用的模型"和"测试假设，这将导致更好地了解启动机制， OA的发展”。非人类灵长类动物是与人类最接近的进化亲属，人体衰老的生理和生物学特征。普通绒猴是最小的绒猴灵长类动物，具有很高的人类翻译潜力，寿命适合研究启动与年龄有关的疾病。在年轻的雄性啮齿动物中，mTOR活性增加有助于OA的发作， mTOR的抑制防止损伤诱导的OA。然而，目前尚不清楚mTOR抑制是否可以减缓在老年人中普遍存在的自然发生的OA的发病机制。此外，尚不清楚mTOR是否与男性一样，在女性中有助于OA的发病机制。为了解决这些知识差距，本建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OA的影响。为为此，我们将使用来自圣安东尼奥内森休克中心的绒猴样本，关节软骨、软骨下骨、滑膜和滑膜OA的高分辨率显微计算机成像成年、老年和老年绒猴队列的断层扫描、组织病理学和免疫组织化学。我们将还评估OA是否伴随与疼痛、不动和死亡率相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关节OA的假设病理学和改变行为与雄性和雌性绒猴的疼痛有关。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绒猴寿命研究。样品将在尸检时收集以评价关节软骨，软骨下骨，滑膜和滑膜。将通过测量下游蛋白质和基因靶标来评价mTOR抑制通过免疫组化和RNA测序。通过完成这个项目，预计我们将发展绒猴，自然发生的年龄相关OA的一种新的翻译模型，我们将确定mTOR和下游途径有助于自然发生的OA的病因学和治疗。建立绒猴作为一个模型，以确定可利用的机制将反过来有助于促进疾病的发展- 用于人类OA的改良疗法。