Delaware Center for Musculoskeletal Research - Wang

特拉华州肌肉骨骼研究中心 - 王

基本信息

批准号：
10854179
负责人：
DAWN M ELLIOTT
金额：
$ 86.7万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10854179
关键词：
1 year old Address Affect Aftercare Age Aging Animal Disease Models Animal Model Animals Astrocytes Behavioral Biochemical Biological Assay Bone Diseases Bone Tissue Bone structure Brain Caregivers Cells Centers of Research Excellence Chronic Disease Clinical Clinical Research Collaborations Combined Modality Therapy Complementary therapies Complex Corpus striatum structure Data Delaware Dementia with Lewy Bodies Development Diffusion Magnetic Resonance Imaging Disease Dorsal Economic Burden Environment Etiology Evaluation Exercise Female Future Goals Grant Health Healthcare Systems Human Immunohistochemistry Impairment Individual Injections Intervention Investigation Knowledge Lead Lewy body pathology Link Magnetic Resonance Imaging Marrow Measures Mechanics Microglia Moderate Exercise Modernization Molecular Motivation Mus Musculoskeletal Neurodegenerative Disorders Neurons Oral Organ Osteoporosis Osteoporotic Outcome Measure Parents Parkinson Disease Patients Pharmacologic Substance Preparation Research Research Design Resources Running Science Serum Markers Skeletal system Societies Specificity System T2 weighted imaging Testing Time Tissues Treatment outcome Woman Work X-Ray Computed Tomography aged alpha synuclein bioimaging body system bone bone loss brain cell brain dysfunction brain magnetic resonance imaging brain tissue cell type clinical practice comparison group comparison intervention density design effective therapy fracture risk imaging biomarker improved in vivo insight interdisciplinary approach male microCT mouse model multidisciplinary neural novel older patient parent project post intervention pre-clinical pre-formed fibril preclinical study response senescence skeletal skeletal disorder skills socioeconomics success synergism tool treadmill treatment group treatment optimization treatment strategy

项目摘要

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.

项目概要衰老是帕金森病 (PD) 和骨骼疾病等神经退行性疾病的主要驱动因素包括骨质疏松症在内的疾病，给医疗保健带来巨大的经济负担和痛苦最近的临床和动物研究表明，这两种疾病具有共同点。一个常见的病因，即衰老细胞的积累，因此，衰老细胞的药物清除。然而，尽管有内在的作用，细胞在这两个领域都在积极地使用各种 senolytic 化合物。由于大脑和骨骼之间的联系，治疗结果的评估一直集中在新出现的证据表明，senolytics 会引起组织和骨骼系统。迫切需要对两个器官的衰老作用进行全面评估。此外，临床实践和临床前研究清楚地表明了适度的好处。运动可以延缓与年龄相关的疾病并改善大脑和骨骼功能。然而，运动之间的协同作用可以与 senolytics 对 PD 和骨质疏松症的治疗起到补充作用。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）、骨力学生物学和运动（Wang）以及小鼠大脑体内 MRI （Chow），我们将测试以下假设：senolytic ABT-263 可以减少两个大脑中的衰老细胞负担基于关键时间窗和细胞类型特异性的老年 PD 小鼠的骨组织和治疗方法减轻衰老细胞的二次损伤，从而产生有利的局部细胞和生化作用我们进一步追求了像跑步机这样的后续运动。跑步提供额外的保护，并与 senolytics 协同作用，保护骨骼和大脑免受为了检验假设，我们的具体目标是全面评估骨骼。以及大脑对单独使用 senolytic ABT-263 治疗或与在细胞中运行的跑步机相结合的治疗的反应，与父项目的对齐：拟议的PD小鼠模型中的组织和脑回路水平。这项工作将测试一种针对帕金森病患者的新型双重治疗，其目标是改善肌肉骨骼功能，母公司COBRE未来计划重点：补充完成将加强协同效应。三个研究小组之间的合作，进一步推动已经建立的合作势头在准备补充材料的过程中，我们将通过家长利用资源和专业知识。 COBRE 和 UD 和 DSU（特拉华州著名的 HBCU）现有的 INBRE 团队设定了以下目标：开发一个更大的多 PI R01 项目，以进一步优化 PD 和骨质疏松症患者的治疗。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

High-Throughput Computing to Automate Population-Based Studies to Detect the 30-Day Risk of Adverse Outcomes After New Outpatient Medication Use in Older Adults with Chronic Kidney Disease: A Clinical Research Protocol.

高通量计算可自动化基于人群的研究，以检测患有慢性肾病的老年人使用新门诊药物后 30 天不良结果的风险：临床研究方案。

DOI：
发表时间：
2024
期刊：
影响因子：
0
作者：
Abdullah, Sheikh S;Rostamzadeh, Neda;Muanda, Flory T;McArthur, Eric;Weir, Matthew A;Sontrop, Jessica M;Kim, Richard B;Kamran, Sedig;Garg, Amit X
通讯作者：
Garg, Amit X

Volume Loss and Recovery in Bovine Knee Meniscus Loaded in Circumferential Tension.

承受圆周张力的牛膝关节半月板的体积损失和恢复。

DOI：
发表时间：
2023-07-01
期刊：
影响因子：
0
作者：
Peloquin, John M;Santare, Michael H;Elliott, Dawn M
通讯作者：
Elliott, Dawn M

Targeted Activation of G-Protein Coupled Receptor-Mediated Ca2+ Signaling Drives Enhanced Cartilage-Like Matrix Formation.

G 蛋白偶联受体介导的 Ca2 信号传导的靶向激活可增强软骨样基质的形成。

DOI：
发表时间：
2022-05
期刊：
影响因子：
0
作者：
McDonough, Ryan C;Price, Christopher
通讯作者：
Price, Christopher

Graft incompatibility between pepper and tomato can be attributed to genetic incompatibility between diverged immune systems.

辣椒和番茄之间的嫁接不相容性可归因于不同免疫系统之间的遗传不相容性。

DOI：
发表时间：
2024-04-01
期刊：
影响因子：
0
作者：
Thomas, Hannah Rae;Gevorgyan, Alice;Hermanson, Alexandra;Yanders, Samantha;Erndwein, Lindsay;Norman;Sparks, Erin E;Frank, Margaret H
通讯作者：
Frank, Margaret H

Yoda1 Enhanced Low-Magnitude High-Frequency Vibration on Osteocytes in Regulation of MDA-MB-231 Breast Cancer Cell Migration.

Yoda1 增强骨细胞低强度高频振动调节 MDA-MB-231 乳腺癌细胞迁移。

DOI：
发表时间：
2022-07-13
期刊：
影响因子：
5.2
作者：
Lin, Chun;Song, Xin;Ke, Yaji;Raha, Arjun;Wu, Yuning;Wasi, Murtaza;Wang, Liyun;Geng, Fei;You, Lidan
通讯作者：
You, Lidan