Administrative Supplement for R01AR080687

R01AR080687 的行政补充

• 批准号: 10858937
• 负责人: Blanka Sharma
• 金额: $ 20.71万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10858937
• 关键词: Address; Administrative Supplement; Adverse effects; Anti-Inflammatory Agents; Antioxidants; Behavior; Biochemical; Biological Availability; Biological Markers; Cells; Clinical; Complement; Degenerative polyarthritis; Development; Disease; Engineering; Evaluation; In Vitro; Inflammation; Intra-Articular Injections; Joints; Manganese; Modeling; Musculoskeletal Diseases; Nerve; Neurons; Nociception; Nociceptors; Oxidative Stress; Pain; Parents; Pathogenesis; Patients; Pattern; Play; Property; Reactive Oxygen Species; Research; Risk; Rodent Model; Spinal Ganglia; Structure; Therapeutic; Tissues; addiction; afferent nerve; antioxidant enzyme; chondroprotection; chronic pain; clinical translation; cost; effective therapy; experience; in vivo; joint destruction; joint injury; mitochondrial dysfunction; nanomaterials; nanoparticle; nerve supply; painful neuropathy; pre-clinical; response; small molecule; therapeutic target; transmission process; treatment response; uptake

ABSTRACT Oxidative stress plays a key role in the pathogenesis of osteoarthritis (OA), contributing directly to tissue breakdown as well as to chronic pain. Attempts to boost antioxidant defenses in the joint have been clinically disappointing - conventional small molecules and exogenously delivered antioxidant enzymes are plagued by poor stability and bioavailability, as well as rapid joint clearance following intra-articular injections. To address these limitations, our parent R01 engineers manganese dioxide nanoparticles (MnO2 NPs), or “nanozymes”, that mimic the reactive oxygen species (ROS) scavenging functions of antioxidant enzymes, but have significant advantages in terms of stability, cost, and bioavailability. Indeed, we demonstrated the properties of these nanomaterials can be tailored for joint tissue retention and cell uptake, which is important for addressing critical barriers to therapeutic delivery in OA. The parent R01 focuses on optimizing the antioxidant activity of the MnO2 NPs, interrogating their chondroprotective and anti-inflammatory mechanisms in vitro, and evaluating their disease-modifying ability in vivo in a rodent model of PTOA. This supplement expands on these studies to include comprehensive evaluation of pain mechanisms in response to MnO2 NP treatment, with particular focus on neuropathic pain. OA patients can experience a combination of nociceptive and neuropathic pain. With nociceptive pain, tissue damage and inflammation leads to activation of nociceptors and pain transmission. Neuropathic pain, however, is caused by damage to the nerves themselves, which can occur with joint injury or as a result of structural changes in the joint as OA progresses. Treatment of neuropathic pain is challenging, as commonly used anti-inflammatories are ineffective, and therapeutic options are limited by risk of addiction and serious adverse effects. Oxidative stress in known to trigger and maintain neuropathic pain, by inducing damage and mitochondrial dysfunction in nerves. Given their pronounced antioxidant functions, stability, and bioavailability, we hypothesize that MnO2 NPs will be effective at alleviating neuropathic pain in PTOA. To lay the groundwork for this scientific direction, this supplement aims to characterize the antioxidant functions of MnO2 NPs with neural cells in vitro, and evaluate biomarkers for neuropathic pain in vivo in response to treatment with MnO2 NP in a PTOA model. These biomarkers, such as joint innervation patterns and cellular composition of the dorsal root ganglion, will complement the behavior analyses, biochemical analyses, and histopathologic analyses in the parent R01. This comprehensive assessment of OA pathogenesis, in terms of joint structure, function, and pain mechanisms, may facilitate successful preclinical to clinical translation of this or other antioxidant strategies for musculoskeletal diseases and chronic pain.

抽象的 氧化应激在骨关节炎 (OA) 的发病机制中起着关键作用，直接影响组织 崩溃以及慢性疼痛。临床上已经尝试增强关节的抗氧化防御能力 令人失望 - 传统的小分子和外源性递送的抗氧化酶受到以下问题的困扰 稳定性和生物利用度差，以及关节内注射后快速关节清除。致地址 这些限制，我们的母公司 R01 工程师设计了二氧化锰纳米粒子（MnO2 NP），或“纳米酶”， 模仿抗氧化酶的活性氧（ROS）清除功能，但具有显着的作用 在稳定性、成本和生物利用度方面具有优势。事实上，我们展示了这些特性 纳米材料可以针对关节组织保留和细胞摄取进行定制，这对于解决关键问题非常重要 OA 治疗传递的障碍。母体R01专注于优化MnO2的抗氧化活性 NPs，在体外探究其软骨保护和抗炎机制，并评估其作用 PTOA 啮齿动物模型体内疾病缓解能力。本补充材料对这些研究进行了扩展，包括 综合评估 MnO2 NP 治疗引起的疼痛机制，特别关注 神经性疼痛。骨关节炎患者可能会同时经历伤害性疼痛和神经性疼痛。和 伤害性疼痛、组织损伤和炎症导致伤害性感受器激活和疼痛传递。 然而，神经性疼痛是由神经本身损伤引起的，这种损伤可能因关节损伤或关节损伤而发生。 随着 OA 的进展，关节结构发生变化。神经性疼痛的治疗具有挑战性，因为 常用的抗炎药无效，治疗选择受到成瘾风险和 严重的不良影响。已知氧化应激可通过诱导损伤来引发和维持神经性疼痛 和神经线粒体功能障碍。 鉴于其显着的抗氧化功能、稳定性和 根据生物利用度，我们假设 MnO2 NPs 将有效减轻 PTOA 的神经性疼痛。铺设 作为这一科学方向的基础，该补充剂旨在表征抗氧化功能 MnO2 NPs 与神经细胞在体外，并评估体内神经病理性疼痛的生物标志物对治疗的反应 PTOA 模型中含有 MnO2 NP。这些生物标志物，例如关节神经支配模式和细胞组成 背根神经节的分析，将补充行为分析、生化分析和组织病理学分析 父 R01 中的分析。这种从关节结构角度全面评估 OA 发病机制的方法， 功能和疼痛机制，可能有助于该或其他药物的临床前成功转化为临床 肌肉骨骼疾病和慢性疼痛的抗氧化策略。