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Activin receptor-based therapies for musculoskeletal disease

基于激活素受体的肌肉骨骼疾病疗法

基本信息

批准号：
8700904
负责人：
Douglas James DiGirolamo
金额：
$ 17.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700904
关键词：
ACVR2 gene ACVR2B gene Activin Receptor Address Advanced Development Age Amputation Attenuated Biological Models Biology Biomechanics Bone Injury Bone Regeneration Bone Tissue Clinical Collaborations Complex Data Defect Development Developmental Biology Environment Fibrosis Foundations Fracture Healing Future Genetic Glean Healed Healthcare Healthcare Systems Histology Homeostasis Impaired wound healing Infection Injury Intervention Limb structure Mediating Mediator of activation protein Modality Modeling Molecular Mouse Strains Mus Muscle Muscle Cells Muscle function Musculoskeletal Musculoskeletal Diseases Musculoskeletal System Myoblasts Natural regeneration Operative Surgical Procedures Orthopedics Osteoblasts Outcome Pathway interactions Physiological Population Quality of life Receptor Signaling Regenerative Medicine Reporting Rodent Role Signal Pathway Skeletal Muscle Skeletal bone Techniques Testing Therapeutic Tissue Engineering Tissues Transgenic Mice Veterans Work base bone bone healing bone mass bone morphogenetic protein 2 combat functional disability functional outcomes gait examination healing insight interdisciplinary collaboration mouse model muscle form muscle regeneration musculoskeletal injury myostatin novel parent grant public health relevance regenerative repaired soft tissue therapeutic target tissue regeneration

项目摘要

DESCRIPTION (provided by applicant): Musculoskeletal diseases and injuries represent a major burden on healthcare systems worldwide, a burden that will only continue to grow as our population continues to age. In addition to the pressing healthcare issues related to musculoskeletal disease, its effects on quality of life can be devastating. This is especially true in the case of traumatic composite injuries involving bone and the surrounding soft tissue. These types of injuries, commonly seen in combat veterans, comprise one of the most challenging environments to regenerate tissue and restore normal function. Deriving from common mesodermal precursors, it is likely that skeletal muscle and bone share common signaling pathways and use these pathways to coordinate homeostasis and regeneration. Previous reports, and our own preliminary data, indicate that activin receptor signaling is a possible candidate to coordinate the mass of these two adjacent tissues, as this pathway exerts analogous regulatory functions in each tissue individually. The studies outlined in this proposal will answer fundamental questions regarding the role of activin receptor signaling in bone and muscle healing, and provide critical insight into the future development of targeted therapeutics for the treatment of traumatic injuries. We envision that it will be possible to apply local biologcs that target activin receptor signaling, such as the soluble activin receptors we have used in the parent grant and the preliminary studies above, to provide a synchronized regenerative approach to composite musculoskeletal injuries. We believe the combined and complementary expertise of our collaborative team in mouse genetics, bone and muscle biology, and regenerative medicine provides a remarkably fertile environment to investigate the physiological mechanisms of muscle-bone interaction, specifically through the activin receptor signaling pathway during healing, so that we can ultimately develop advanced therapeutics to regenerate bone and muscle in devastating traumatic injuries.

描述(申请人提供)：肌肉骨骼疾病和损伤是全球医疗保健系统的主要负担，随着我们人口的继续老龄化，这一负担只会继续增长。除了与肌肉骨骼疾病相关的紧迫医疗问题外，它对生活质量的影响可能是毁灭性的。这一点尤其正确在涉及骨骼和周围软组织的创伤性复合损伤的情况下。这些类型的创伤通常见于退伍军人，构成了再生组织和恢复正常功能最具挑战性的环境之一。骨骼肌和骨骼起源于共同的中胚层前体，很可能共享共同的信号通路，并使用这些通路来协调动态平衡和再生。以前的报道和我们自己的初步数据表明，激活素受体信号可能是协调这两个相邻组织质量的候选信号，因为这一途径在每个组织中分别发挥类似的调节功能。这项提案中概述的研究将回答有关激活素受体信号在骨骼和肌肉愈合中的作用的基本问题，并为创伤损伤治疗的靶向疗法的未来发展提供重要的见解。我们设想有可能应用针对激活素受体信号转导的局部生物制剂，例如我们在父母资助和上述初步研究中使用的可溶性激活素受体，为复合性肌肉骨骼损伤提供一种同步再生的方法。我们相信，我们的合作团队在小鼠遗传学、骨骼和肌肉生物学以及再生医学方面的综合和互补专业知识为研究肌肉-骨骼相互作用的生理机制提供了一个非常肥沃的环境，特别是通过愈合过程中的激活素受体信号通路，从而使我们最终能够开发先进的治疗方法，在毁灭性的创伤中再生骨骼和肌肉。