Hif-1 as an antagonist of load-induced bone formation

描述(由申请人提供)： 我致力于骨生物学基础科学的学术生涯，专注于机械信号调节骨骼内稳态的机制。我的长期目标是成为退伍军人管理局骨生物学领域的领导者。我在机械转导模型方面有很强的背景，并在我的博士后培训期间获得了关于基因改变小鼠的特征的经验。在这个职业发展奖的申请中，我将应用我的科学背景的这两个方面来研究Wnt/2-catenin信号在骨骼对机械负荷的反应中的作用。2-连环蛋白在体内和体外均可被机械信号激活，但该转录因子的激活机制尚不清楚。具体目的1将确定Wnt共受体LRP5和LRP6在机械负荷后2-连环蛋白激活和骨形成中的作用。然后，我们将研究调节2-连环蛋白活性的机制。初步数据表明，机械信号可增加缺氧诱导因子-11的表达，该因子可能抑制2-连环蛋白的活性。特定目的2将表征骨骼特异性缺失Hif-11在负荷诱导成骨和Wnt/2-catenin信号转导中的作用。每个特定的目的都利用体外和体内研究相结合的方法来确定这些因素在骨细胞机械转导中的作用。我坚信，这项工作的完成将为物理刺激调节骨量的机制提供新的见解，并导致旨在改善退伍军人骨强度的新治疗策略的开发。此外，这些研究的结果将构成更大的功绩审查拨款的基础，再加上克莱门斯博士和塞门扎博士提供的指导以及实验室管理、资质和科学陈述方面的额外培训，应该可以确保我作为一名独立的退伍军人管理局研究员取得成功。

DESCRIPTION (provided by applicant): I am committed to an academic career in the basic science of bone biology with a focus on the mechanisms by which mechanical signals regulate bone homeostasis. My long-term goal is to become a leader at the VA in the field of bone biology. I have a strong background in models of mechanotransduction and have gained experience during my postdoctoral training in the characterization of genetically-altered mice. In this Career Development Award Application, I will apply these two aspects of my scientific background to examine the role of Wnt/2-catenin signaling in the response of bone to mechanical loads. 2-catenin is activated by mechanical signals both in vivo and in vitro, but the mechanism by which this transcription factor is activated remains unclear. Specific Aim 1 will determine the role of the Wnt co-receptors Lrp5 and Lrp6 in mediating the activation of 2-catenin and bone formation after mechanical loading. We will then examine mechanisms by which 2-catenin activity is regulated. Preliminary date suggests that the expression of hypoxia-inducible factor-11 is increased by mechanical signals and that this factor may act to inhibit 2-catenin activity. Specific aim 2 will characterize the effect of skeletal specific-deletion of Hif-11 on load induced osteogenesis and Wnt/2-catenin signaling. Each specific aim utilizes a combination of in vitro and in vivo studies to determine the roles of these factors in bone cell mechanotransduction. It is my strong belief that the completion of this work will provide new insights into the mechanisms by which physical stimuli regulate bone mass and lead to the development of novel therapeutic strategies designed to improve bone strength in veterans. Further, the results of these studies will form the basis for a larger Merit Review grant, and when combined with the mentorship provided by Dr. Clemens and Dr. Semenza and additional training in laboratory management, grantsmanship, and scientific presentation should ensure my success as an independent VA investigator.