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Pharmacologic Activation of the Hypoxia Inducible Factor Pathway in Bone Healing

骨愈合中缺氧诱导因子途径的药理学激活

基本信息

批准号：
7496562
负责人：
Shawn Robert Gilbert
金额：
$ 18.33万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-11 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7496562
关键词：
Acute Angiogenesis Promoter Animal Model Biological Assay Biomechanics Brain Cells Clinical Clinical Trials Collagen Cultured Cells Defect Deferoxamine Deformity Degradation Pathway Development Distraction Osteogenesis Elevation Evaluation Face Failure Fracture Healing Frustration Genetic Healed Heart Histologic Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway Immunohistochemistry Impaired wound healing In Vitro Infection Intervention Ischemia Kidney Lead Limb structure Luciferases Mesenchymal Stem Cells Methods Mimosine Modeling Mus Natural regeneration Operative Surgical Procedures Orthopedics Osteogenesis Pathway interactions Patients Phase Physicians Procedures Procollagen-Proline Dioxygenase Public Health Rate Rattus Reporter Screening procedure Secondary to Skeletal system Skin Surgeon Testing Toxic effect Trauma Vascular Endothelial Growth Factors Vascularization angiogenesis base bone bone healing distraction healing improved in vivo mouse model neovascularization novel postnatal prevent reconstruction repaired research study response sample fixation small molecule tibia tool

项目摘要

DESCRIPTION (provided by applicant): Distraction osteogenesis is a powerful tool for limb reconstruction. However, frequent problems, obstacles and complications make application of the methods difficult for patients and physicians. Among these issues, delayed or failed bone healing can be particularly problematic, requiring prolonged external fixation and/or additional procedures. A key feature of distraction is the induction of angiogenesis. Prior studies have shown that hypoxia inducible factor (HIF), a key regulator of the response to altered oxygenation and promoter of angiogenesis, is strongly induced during distraction osteogenesis. Further, we have demonstrated that increased HIF activation in bone in a mouse model increases postnatal bone acquisition. In this proposal, we will test the hypothesis that increased activation of HIF pathway will alter bone healing in distraction osteogenesis. We will use pharmacologic intervention to block HIF degradation, resulting in increased HIF activation and increased activation of downstream targets influencing angiogenesis. In aim 1, we will evaluate pharmacologic agents for potential to increase HIF activation and upregulate downstream targets in vitro, and select the most promising for evaluation in vivo. In the second aim, the agents will be applied locally to the distraction zone in mice undergoing distraction osteogenesis of the tibia. We will examine the distracted bones histologically, radiographically and biomechanically. Also, a second experimental group will undergo distraction at a supraoptimal rate, a maneuver that leads to delayed or non healing, to test whether increased HIF activation can allow faster distraction or lead to healing of non-unions.

描述（由申请人提供）：牵张成骨是肢体重建的有力工具。然而，频繁的问题，障碍和并发症使得患者和医生难以应用这些方法。在这些问题中，延迟或失败的骨愈合可能特别成问题，需要延长的外部固定和/或额外的手术。牵张的一个关键特征是诱导血管生成。以前的研究表明，低氧诱导因子（HIF），一个关键的调节器的反应改变氧和促进血管生成，强烈诱导在牵张成骨。此外，我们已经证明，在小鼠模型中，骨中HIF活化的增加会增加出生后的骨获得。在这个建议中，我们将测试的假设，增加激活的缺氧诱导因子途径将改变骨愈合牵引成骨。我们将使用药物干预来阻断HIF降解，导致HIF活化增加和影响血管生成的下游靶点的活化增加。在目标1中，我们将评估药理学试剂在体外增加HIF活化和上调下游靶点的潜力，并选择最有希望的用于体内评估。在第二个目标中，将试剂局部应用于经历胫骨牵张成骨的小鼠的牵张区。我们将从组织学、放射学和生物力学方面对牵引骨进行检查。此外，第二个实验组将以超最佳速率进行牵引，这是一种导致延迟愈合或不愈合的策略，以测试增加HIF激活是否可以允许更快的牵引或导致不愈合愈合。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice.

脯氨酰羟化酶抑制剂可增加小鼠股骨骨折后的新血管生成和愈伤组织形成。

DOI：
10.1002/jor.20886
发表时间：
2009-10
期刊：
JOURNAL OF ORTHOPAEDIC RESEARCH
影响因子：
2.8
作者：
Shen, Xing;Wan, Chao;Ramaswamy, Girish;Mavalli, Mahendra;Wang, Ying;Duvall, Craig L.;Deng, Lian Fu;Guldberg, Robert E.;Eberhart, Alan;Clemens, Thomas L.;Gilbert, Shawn R.
通讯作者：
Gilbert, Shawn R.