Hypoxia inducible factor 1alpha--fracture repair

缺氧诱导因子1α--骨折修复

• 批准号: 6632763
• 负责人: MICHAEL HADJIARGYROU
• 金额: $ 7.53万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632763
• 关键词: angiogenesis; bone regeneration; erythropoiesis; femur fracture; gene induction /repression; hypoxia; in situ hybridization; laboratory mouse; laboratory rat; messenger RNA; northern blottings; transcription factor; vascular endothelial growth factors; vasodilation; western blottings

DESCRIPTION (Taken from the application): Despite a wealth of information regarding hypoxia and angiogenesis during fracture repair, the underlining molecular events responsible for these critical early processes remain unknown. With the recent technological advances in molecular biology and the identification of thousands of genes, it is now possible to more clearly examine the precise molecular events that underlie the fracture repair process. In essence, we strongly believe that key early stage processes, including hypoxia and angiogenesis, are ultimately responsible for determining the success (or failure) of the healing process. Thus, we propose the hypothesis that during the early stages of fracture healing, hypoxia resulting from the inevitable disruption of the bone's blood supply, induces hypoxia inducible factor I (HIF-1a), which in turn up-regulates transcription of a cascade of downstream genes that directly promote angiogenesis. The objective of this three year study is to test the hypothesis that the up-regulation of the transcription factor, HIF-la, is critical to the establishment of neovascularization within areas of chondrogenesis and endochondral ossification in the fracture callus. Our preliminary data show that HIF-la, as well as a number of angiogenic-related genes (i.e. vascular endothelial growth factor [VEGF], CYR61), are up-regulated during the stages of fracture healing, providing strong supporting evidence for our hypothesis. Experiments will be performed to systematically extend these findings through four specific aims that utilize the established in vivo femur fracture model to determine the temporal and spatial expression levels of: (i) HIF-1a (ii) its target genes known to play a role in angiogenesis (VEGF), vasodilation (nitric oxide synthase NOS, heme oxygenase HO1, and erythopoiesis (erythropoietin RPO, tranferrin), and to directly compare the (iii) angiogenesis (neovascularization) and (iv) structural integrity (strength and stiffness) of the fracture callus and healing femurs, respectively, in HIF-1a partially deficient (+/-) mice to that of their wild type (+/+) littermates. These studies will provide unique insight into critical early-stage events, and help define etiologic factors that may contribute to the incidence of delayed healing, particularly in the case of the molecular components (i.e. HIF-l a) involved in hypoxia and angiogenesis.

描述（摘自应用程序）：尽管有大量信息 关于骨折修复过程中的缺氧和血管生成，强调 负责这些关键早期过程的分子事件仍然未知。 随着近年来分子生物学技术的进步和 识别数千个基因，现在可以更清楚地 检查骨折修复过程中的精确分子事件。 从本质上讲，我们坚信关键的早期阶段流程，包括 缺氧和血管生成，最终决定了 愈合过程的成功（或失败）。因此，我们提出假设 在骨折愈合的早期阶段，由于骨折引起的缺氧 不可避免地破坏骨骼的血液供应，导致缺氧 因子 I (HIF-1a)，它反过来上调一系列级联的转录 直接促进血管生成的下游基因。此举的目的 为期三年的研究旨在检验以下假设： 转录因子 HIF-1a 对于建立 软骨形成和软骨内骨化区域内的新生血管形成 在骨折愈伤组织中。我们的初步数据表明，HIF-la 以及 血管生成相关基因（即血管内皮生长因子）的数量 [VEGF]、CYR61) 在骨折愈合阶段上调， 为我们的假设提供了有力的支持证据。实验将是 通过四个具体目标系统地扩展这些发现 利用已建立的体内股骨骨折模型来确定 (i) HIF-1a (ii) 其靶基因的时间和空间表达水平 已知在血管生成（VEGF）、血管舒张（一氧化氮）中发挥作用 合酶 NOS、血红素加氧酶 HO1 和红细胞生成（促红细胞生成素 RPO、 转铁蛋白），并直接比较（iii）血管生成 （新生血管）和（iv）结构完整性（强度和刚度） HIF-1a 中的骨折愈伤组织和愈合股骨分别部分 缺陷（+/-）小鼠与其野生型（+/+）同窝小鼠相比。这些 研究将为关键的早期事件提供独特的见解，并帮助 明确可能导致延迟发生的病因 愈合，特别是在分子成分（即 HIF-1a）的情况下 参与缺氧和血管生成。