Role of Hox Genes in Integration of the Musculoskeletal System in Development

Hox 基因在发育中肌肉骨骼系统整合中的作用

• 批准号: 8840889
• 负责人: Deneen M Wellik
• 金额: $ 34.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840889
• 关键词: Address; Adult; Alleles; Biology; Biomedical Engineering; Cartilage; Connective Tissue; Data; Defect; Development; Developmental Biology; Disease; Elements; Event; Forelimb; Fracture; Gene Expression; Genes; Genetic Determinism; Goals; Growth; Healed; Hereditary Disease; Hindlimb; Histocompatibility Testing; Indium; Individual; Injury; Knowledge; Laboratories; Limb Development; Limb structure; Lower Extremity; Mediating; Mesenchyme; Molecular; Mus; Muscle; Musculoskeletal; Musculoskeletal Development; Musculoskeletal System; Pathway interactions; Patients; Pattern; Pattern Formation; Play; Process; Proliferating; Proteins; Regenerative Medicine; Regulation; Reporter; Reporting; Research; Role; Skeleton; Stereotyping; Study models; Tendon structure; Testing; Tissues; Translating; Upper Extremity; Work; Wound Healing; base; bone; cell type; gene function; healing; in vivo; injury and repair; innovation; mutant; novel; regenerative; regenerative therapy; repaired; response to injury; skeletal; skeletal tissue; spatiotemporal; tissue repair; tool

DESCRIPTION (provided by applicant): A significant amount of data exists regarding the formation and differentiation of muscle, bone and tendon tissue individually, but little is understood regarding molecular mechanisms that allow these tissues to make appropriate connections with one another. This knowledge is critical for establishing useful therapies to repair these tissues after disruption from injury or disease. Hox genes perform fundamental roles in patterning the skeleton, but new preliminary data shows that Hox gene expression in the developing limb is not restricted to skeletal tissue, and these genes also appear to play less anticipated roles in patterning tendon and muscle tissue as well as in the integration of all three tissue types. Recent data additionally that shows that these genes are highly up-regulated following injury, suggesting a role in the healing and remodeling that occurs in response to injury. The long-term goal of this research is to understand how Hox genes regulate the region- specific formation and integration of the musculoskeletal system and how this information can be used to inform regenerative therapies following injury or disease. The objective of this proposal is to achieve an understanding of the cellular mechanisms of Hox function in the development and integration of muscle, tendon and bone in the developing forelimb and how these mechanisms are redeployed in response to injury. The central hypothesis is that Hox11 genes function to direct the patterning and the integration of the muscle, tendon and cartilage in the developing limb and that these genes are up-regulated in response to injury to allow proper repair and remodeling in vivo. How Hox11 genes contribute to the formation and patterning of muscle groups, tendons and cartilage elements within the developing limb will be assessed using existing null alleles and fluorescent reporter lines. The spatiotemporal control of Hox-mediated patterning and the establishment of connectivity in the musculoskeletal system will be examined by conditionally ablating Hox function using spatial and temporally restricted Cre deletor lines. Finally, the roles for Hox genes in tissue repair and skeletal remodeling will be determined by conditionally ablating Hox function in adulthood (after proper musculoskeletal patterning has been achieved) and examining the effects of loss of Hox function on fracture repair and subsequent skeletal remodeling. The contribution of the proposed research is significant because critical new knowledge regarding the regional regulation musculoskeletal integration will be gained, the tissue(s) from which this information is transmitted will be defined, and how these factors are redeployed in adulthood to repair injuries will be determined. The research proposed in this application is innovative in identifying factors and cell types involved in the integration of individual components of the musculoskeletal system as well as in the novel tools generated to allow an understanding of the function of Hox genes in properly patterned adult tissue during injury repair processes. Together, the information gained from these studies will provide a paradigm-shifting understanding of Hox function in musculoskeletal biology.

描述（由申请人提供）：有关肌肉，骨骼和肌腱组织的形成和分化的大量数据，但几乎没有理解有关允许这些组织可以彼此进行适当连接的分子机制的理解。这些知识对于建立有用的疗法来修复受伤或疾病后修复这些组织至关重要。 HOX基因在对骨骼的模式中发挥了基本作用，但是新的初步数据表明，发育中的肢体中的HOX基因表达不仅限于骨骼组织，而且这些基因在图案肌腱和肌肉组织以及所有三种组织类型的整合中似乎也扮演着较低的预期作用。最近的数据还表明，这些基因在受伤后高度上调，这表明在响应损伤的愈合和重塑中起作用。这项研究的长期目标是了解HOX基因如何调节肌肉骨骼系统的特定区域形成和整合，以及如何使用该信息来告知损伤或疾病后再生疗法。该提案的目的是了解HOX功能在发育前肢中肌肉，肌腱和骨骼的发展和整合中的细胞机制，以及这些机制如何响应损伤而重新部署。中心假设是HOX11基因的作用是指导发育中的肢体中肌肉，肌腱和软骨的模式和整合，并且这些基因响应损伤而上调以允许在体内进行适当的修复和重塑。 HOX11基因如何使用现有的零等位基因和荧光记者线来评估发育肢体内肌肉群，肌腱和软骨元素的形成和模式。 HOX介导的图案的时空控制和在肌肉骨骼系统中的建立将通过使用空间和时间限制的CRE删除器线进行有条件地擦除HOX函数来检查肌肉骨骼系统中的连通性。最后，HOX基因在组织修复和骨骼重塑中的作用将通过在成年期有条件地消除HOX功能（在达到适当的肌肉骨骼模式之后）确定，并检查HOX功能损失对分裂修复和随后的骨骼重塑的影响。拟议研究的贡献很重要，因为将获得有关区域调节肌肉骨骼融合的关键新知识，将定义该信息的组织，以及如何在修复伤害的富裕中重新部署这些因素。本应用中提出的研究是在识别肌肉骨骼系统各个组成部分以及生成的新工具中涉及的因素和细胞类型方面具有创新性的，旨在了解HOX基因在损伤修复过程中适当构图的成人组织中的功能。从这些研究中获得的信息一起将提供对肌肉骨骼生物学中HOX功能的范式转变的理解。