Delaware Center for Musculoskeletal Research - Wang

项目总结 衰老是导致帕金森氏病(PD)和骨骼肌等神经退行性疾病的主要原因 包括骨质疏松症在内的疾病，这些疾病对医疗保健造成重大经济负担和痛苦 系统、病人和他们的照顾者。最近的临床和动物研究表明，这两种疾病是相同的。 一种常见的病因，即衰老细胞的堆积。因此，药物清除衰老 细胞在这两个领域都在使用各种感光分解化合物进行积极的研究。然而，尽管存在内在的 大脑和骨骼之间的联系，对治疗结果的评估一直狭隘地集中在 要么是神经系统，要么是骨骼系统。新出现的证据表明，感觉剂会引发组织--和 特定于细胞的反应。迫切需要对这两个器官的感觉神经分解作用进行全面评估。 系统。此外，临床实践和临床前研究清楚地表明了中度治疗的好处。 运动有助于延缓年龄相关性疾病，改善大脑和骨骼功能。因此，锻炼可以 补充抗衰老药物治疗帕金森病和骨质疏松症。然而，运动之间的协同作用 而感觉剂还没有被研究过。为了填补这一知识空白，我们提出了一个团队科学项目， 将采取多学科的方法。利用团队在PD方面的互补专业知识 动物模型和感觉神经分解(KIM)、骨机械生物学和运动(WANG)和小鼠脑活体核磁共振 (Chow)，我们将检验这样的假设，即抗衰老的ABT-263减少了双侧大脑中衰老细胞的负担。 基于临界时间窗和细胞类型特异性的老年帕金森病小鼠的骨组织和治疗 减轻衰老细胞的二次损伤，促进局部细胞和生化 大脑和骨骼细胞的环境。我们进一步假设，随后的运动，如跑步机 跑步提供额外的保护，并与感觉剂协同作用，保护骨骼和大脑免受 老年帕金森病小鼠的退行性变。为了验证这些假设，我们的具体目标是对骨骼进行全面评估 以及对单独或与跑步机一起在细胞内跑步的感觉剂ABT-263治疗的大脑反应， 在一种新的帕金森病小鼠模型中，组织和脑电路水平。与父项目对齐：建议的 工作将测试一种新的帕金森病患者的双重治疗方法，目的是改善肌肉骨骼功能， 母眼镜蛇的焦点。未来计划：补充计划的完成将加强协同效应 三个研究小组之间的合作并进一步推动已经建立的合作势头 在准备增刊的过程中。我们将通过母公司利用资源和专业知识 科布雷和现有的INBRE在UD和DSU，特拉华州著名的HBCU。这个团队设定了他们的目标是 开发更大的多PI R01项目，以进一步优化对帕金森病和骨质疏松症患者的治疗。

PROJECT SUMMARY Aging is a major driver of neurodegenerative disorders such as Parkinson’s disease (PD) and skeletal diseases including osteoporosis, which inflict significant economic burdens and suffering on the healthcare system, patients, and their caregivers. Recent clinical and animal studies suggest that the two diseases share a common etiology, i.e., the accumulation of senescent cells. Thus, pharmaceutical clearance of senescent cells is being actively pursued in both fields using various senolytic compounds. However, despite the intrinsic links between the brain and bone, the evaluation of the treatment outcomes has been narrowly focused on either the neural or skeletal system alone. Emerging evidence demonstrates that senolytics elicit tissue- and cell-specific responses. There is an urgent need for a holistic evaluation of senolytic effects on both organ systems. Furthermore, clinical practice and preclinical investigation clearly show the benefits of moderate exercise in delaying age-associated diseases and improving brain and bone functions. Thus, exercise could be complementary to senolytics for PD and osteoporosis treatment. However, the synergy between exercise and senolytics has not been investigated. To fill this knowledge gap, we propose a team science project that will take a multi-disciplinary approach. Taking the advantage of the team’s complementary expertise in PD animal models and senolytics (Kim), bone mechanobiology and exercise (Wang), and mouse brain in vivo MRI (Chow), we will test the hypothesis that senolytic ABT-263 decreases the senescent cell burden in both brain and bone tissues of aged PD mice based on a critical time-window and cell-type specificity, and the treatment mitigates the secondary damages from senescent cells, leading to favorable local cellular and biochemical environments for brain and skeletal cells. We further hypothesize that subsequent exercise like treadmill running provides additional protection and acts in synergy with senolytics in protecting bone and brain from degeneration in aged PD mice. To test the hypotheses, our specific aim is to holistically evaluate the bone and brain responses to senolytic ABT-263 treatment alone or in combination with treadmill running at the cell, tissue, and brain circuit levels in a novel PD mouse model. Alignment with the Parent Project: The proposed work will test a novel dual-treatment in PD patients with the goal of improving the musculoskeletal function, a focus of the parent COBRE. Future plans: The completion of the supplement will strengthen the synergy among the three research groups and further propel the momentum of collaboration that has been built up during the preparation of the supplement. We will leverage the resources and expertise through the parent COBRE and existing INBRE at UD and DSU, a prominent HBCU in Delaware. The team sets their goal of developing a larger multi-PI R01 project to further optimize treatments for PD and osteoporotic patients.