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

将 HIF-2 信号通路作为骨辐射防护策略

• 批准号: 10665782
• 负责人: Colleen Wu
• 金额: $ 35.42万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665782
• 关键词: Ablation; Adipocytes; Adipose tissue; Anatomy; Biology; Bone Development; Bone Marrow; Cancer Patient; Cell Culture Techniques; Cell Survival; Cell physiology; Cells; Clinical; Combined Modality Therapy; DNA Damage; Data; Disease-Free Survival; Encapsulated; Exposure to; FDA approved; Fracture; Genetic; Genetically Engineered Mouse; Goals; Homeostasis; Hypoxia; Hypoxia Inducible Factor; Impairment; In Vitro; Ionizing radiation; Knowledge; Label; Location; Malignant Neoplasms; Marrow; Mesenchymal Stem Cells; Minerals; Modality; Molecular; Molecular Target; Mus; Mutant Strains Mice; Osteoblasts; Oxygen; Pathology; Patients; Phase II/III Clinical Trial; Phenotype; Population; Radiation; Radiation Protection; Radiation exposure; Radiation induced damage; Radiation therapy; Radiation-Protective Agents; Reporter; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Stress; Testing; Therapeutic; Tissues; Tomatoes; Treatment Efficacy; Treatment Protocols; absorption; bHLH-PAS factor HLF; bone; bone loss; cancer cell; cancer therapy; cell type; cellular targeting; defined contribution; efficacy evaluation; experimental study; fracture risk; head-to-head comparison; improved; inhibitor; lipid biosynthesis; mouse model; nanocarrier; novel; patient population; pharmacologic; prevent; radiation mitigation; radioprotected; response; targeted delivery; therapeutic target; therapeutically effective; transcription factor; tumor

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.

项目摘要 放射疗法有效消除了恶性细胞，但对肿瘤周围健康组织的损害 仍然是一个持续的临床问题。实际上，接受放射治疗的癌症患者增加了 与接受相同治疗方案但未受到治疗方案的人相比，骨折的风险 进行放射疗法。不幸的是，使用抗吸收剂（例如双磷酸盐）并未显着 减少该患者人群的不足骨折。由于这些原因，我们的长期目标是确定 可以在治疗骨骼的辐射保护方面可以利用的独特细胞和分子机制。 值得注意的是，骨微环境（BME）的特征是低氧张力或缺氧。响应 这种外部刺激，BME中的许多细胞类型都激活了缺氧诱导因子（HIF）信号，以促进 细胞存活。虽然需要HIF信号通路的激活才能维持健康的骨骼，但贡献 辐射诱导的骨损伤期间缺氧/HIF信号传导尚未得到很好的定义。有趣的是，我们展示了 与非 - 辐照对照。此外，初步数据表明，MMP在低氧区域发现并响应 通过稳定HIF-2来缺氧。令人惊讶的是，尽管MMP人群中HIF-2的有条件消融没有改变 骨稳态，它确实可以防止辐射暴露后防止骨质流失。由于这些原因，我们 总体假设是HIF-2的遗传学和药理抑制作用将作为辐射保护 通过维持MMP的数量，可以改善辐射暴露后减轻骨骼损伤的机制 在压力引起的损伤后，这可以在功能上有助于骨骼。为了检验我们的假设，我们将利用 基因工程小鼠模型，体外细胞培养实验和新颖的组合 抑制BME中HIF-2信号通路的药理方法。目前，没有FDA 批准的药物减轻辐射引起的骨质流失，因此这些研究不仅会扩大我们的 骨骼生物学的基本知识，但还将满足识别治疗靶标的临床需求 这将减轻放射疗法后的骨损伤。