Delaware Center for Musculoskeletal Research - Wang

项目摘要 衰老是神经退行性疾病如帕金森病（PD）和骨骼肌退行性疾病的主要驱动因素。 包括骨质疏松症在内的疾病，这些疾病给医疗保健带来了巨大的经济负担和痛苦 系统、患者及其护理人员。最近的临床和动物研究表明，这两种疾病共享 一种常见的病因学，即，衰老细胞的积累。因此，药物清除衰老 在这两个领域中，使用各种衰老清除化合物积极地研究细胞。然而，尽管内在 由于大脑和骨骼之间的联系，治疗结果的评价一直局限于 无论是神经系统还是骨骼系统。新出现的证据表明，senolytics引起组织-和 细胞特异性反应。迫切需要对衰老清除剂对这两种器官的作用进行整体评价 系统.此外，临床实践和临床前研究清楚地表明了适度的 运动可以延缓与年龄相关的疾病，改善大脑和骨骼功能。因此，锻炼可以 补充用于PD和骨质疏松症治疗的senolytics。然而，运动与运动之间的协同作用 和senolytics尚未被调查。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senolytics（Kim），骨机械生物学和运动（Wang），以及小鼠脑的体内MRI （Chow），我们将检验衰老清除剂ABT-263降低两个脑中衰老细胞负荷的假设。 和骨组织的治疗， 减轻衰老细胞的二次损伤，导致有利的局部细胞和生化 大脑和骨骼细胞的生长环境。我们进一步假设，随后的运动，如跑步机， 跑步提供了额外的保护，并与senolytics协同作用，保护骨骼和大脑免受 老年PD小鼠的退化。为了验证这些假设，我们的具体目标是全面评估骨骼 以及对单独的衰老清除剂ABT-263治疗或与在细胞上跑步机联合治疗的脑反应， 组织和脑回路水平。与母项目保持一致：拟议的 这项工作将测试一种新的双重治疗PD患者的目标是改善肌肉骨骼功能， COBRE的核心。未来计划：补齐完成将加强协同 进一步推动三个研究小组之间业已建立的合作势头， 在补充的过程中。我们将通过母公司利用资源和专业知识， COBRE和UD和DSU的现有INBRE，这是特拉华州一个著名的HBCU。该团队设定了他们的目标， 开发更大的多PI R 01项目，以进一步优化PD和帕金森病患者的治疗。

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.