Targeting the HIF-2 Signaling Pathway as a Radioprotective Strategy for Bone

项目总结 虽然放射治疗可以有效地消除恶性肿瘤细胞，但对肿瘤周围健康组织的损害 仍然是一个长期存在的临床问题。事实上，接受放射治疗的癌症患者的 与接受相同治疗方案但未接受治疗的患者相比，骨折的风险 到放射治疗。不幸的是，像双磷酸盐这样的抗吸收药物的使用并不显著。 减少这类患者的不完全性骨折。出于这些原因，我们的长期目标是确定 独特的细胞和分子机制，可用于治疗骨的辐射防护。 值得注意的是，骨微环境(BME)的特点是低氧压或低氧。作为对.的回应 这种外界刺激，使多种细胞类型的BME激活缺氧诱导因子(HIF)信号转导 细胞存活。虽然激活HIF信号通路是维持骨骼健康所必需的，但 放射性骨损伤过程中低氧/缺氧诱导因子信号转导机制的研究尚不清楚。有趣的是，我们展示了 与未照射的骨相比，照射的骨显示多潜能间充质祖细胞(MMPs)的减少 照射后的对照组。此外，初步数据显示，在缺氧区发现了MMPs，并对 通过稳定HIF-2缺氧。值得注意的是，尽管有条件地消融一组MMP中的HIF-2并没有改变 骨骼动态平衡，它确实起到了防止辐射后骨质流失的作用。基于这些原因，我们的 最重要的假设是，HIF-2的遗传和药物抑制将起到辐射防护的作用 减轻辐射后骨损伤的机制，部分是通过维持MMPs的数量 在应力诱导的损伤后，可以在功能上对骨骼做出贡献。为了测试我们的假设，我们将使用一个 基因工程小鼠模型、体外细胞培养实验和新技术的结合 抑制BME中HIF-2信号通路的药理学方法。目前，还没有FDA 被批准用于减轻辐射引起的骨丢失的药物，因此这些研究不仅将扩大我们的 骨生物学的基本知识，但也将填补未满足的临床需要，以确定治疗目标 这将改善放射治疗后的骨损伤。

PROJECT SUMMARY While radiation therapy effectively eliminates malignant cells, damage to healthy tissue surrounding tumors remains a persistent clinical issue. Indeed, cancer patients who receive radiation treatment have an increased risk for fracture when compared to those who undergo the same treatment regimen but who are not subjected to radiotherapy. Unfortunately, the use of antiresorptive agents such as bisphosphates does not significantly reduce insufficiency fractures for this patient population. For these reasons, our long-term goal is to identify unique cellular and molecular mechanisms that can be therapeutically exploited for the radioprotection of bone. Notably, the bone microenvironment (BME) is characterized by low oxygen tension or hypoxia. In response to this external stimulus, many cell types in the BME activate hypoxia inducible factor (HIF) signaling to facilitate cell survival. While activation of the HIF signaling pathway is required to maintain healthy bone, the contribution of hypoxia/HIF signaling during radiation induced bone damage has not been well defined. Intriguingly, we show irradiated bones show a decrease in multipotent mesenchymal progenitors (MMPs) when compared to non- irradiated controls. Moreover, preliminary data shows that MMPs are found in hypoxic regions and respond to hypoxia by stabilizing HIF-2. Strikingly, while conditional ablation of HIF-2 in a population of MMPs did not alter bone homeostasis, it did serve to protect against bone loss after radiation exposure. For these reasons, our overarching hypothesis is that genetic and pharmacological inhibition of HIF-2 will serve as a radioprotective mechanism to ameliorate bone damage after radiation exposure, in part, by maintaining the number of MMPs that can functionally contribute to bone after stress induced damage. To test our hypothesis, we will utilize a combination of genetically engineered mouse models, in vitro cell culture experiments, and novel pharmacological approaches to inhibit the HIF-2 signaling pathway in the BME. Currently, there are no FDA approved agents to mitigate radiation induced bone loss, hence these studies will not only expand our fundamental knowledge of bone biology but will also fill an unmet clinical need to identify therapeutic targets which will ameliorate bone damage after radiotherapy.