Cancer Therapy-induced Long-term Bone Marrow Injury

描述（由申请人提供）：由于癌症的早期检测和治疗的显著改善，癌症幸存者的数量正在增加。不幸的是，长期癌症幸存者患癌症治疗相关晚期效应的风险增加，包括 电离辐射（IR）和化疗诱导的长期骨髓（LT-BM）损伤。LT-BM损伤主要归因于造血干细胞（HSC）中氧化应激和衰老的选择性诱导。本项目的目的是利用我们的充分表征的全身照射（TBI）或化疗诱导的LT-BM损伤小鼠模型来（1）鉴定HSC中活性氧（ROS）的主要细胞来源，（2）阐明HSC中ROS的产生是如何调节的，和（3）开发一种基于机制的策略，其可以通过选择性抑制HSC中ROS的产生来有效地抑制IR和化疗诱导的HSC衰老和LT-BM抑制。具体而言，待检验的假设是：（1）来源于NADPH氧化酶4（NOX 4）的ROS主要负责介导IR和化疗诱导的HSC衰老，以及（2）抑制NOX 4可开发为有效减少IR和化疗诱导的LT-BM损伤的新型治疗策略。三个具体的目标将追求测试这些假设。目的1：确定NOX 4是否主要负责HSC中ROS的产生以介导TBI诱导的HSC衰老和LT-BM损伤。目标二：研究哺乳动物雷帕霉素靶蛋白（mTOR）-低氧诱导因子1（HIF 1）通路的激活是否介导了HSC中IR诱导的NOX 4上调。目标3：确定用NOX抑制剂抑制NOX 4活性或用mTOR抑制剂抑制NOX 4上调是否可以有效抑制不仅由IR而且由化疗诱导的HSC衰老和LT-BM损伤。这些研究将有助于深入了解IR和化疗诱导的LT-BM损伤的发病机制。这些见解将有助于开发更有效的策略来预防和减轻IR和化疗诱导的LT-BM毒性。由于N 0X 4的表达增加和mTOR的异常激活涉及肿瘤发生和肿瘤对治疗的抗性，因此N 0X 4或mTOR的靶向抑制可以为癌症患者提供减少IR和化疗诱导的LT-BM抑制同时增加肿瘤对癌症治疗的反应的双重益处。

DESCRIPTION (provided by applicant): Due to significant improvements in the early detection and the treatment of cancer, the number of cancer survivors is increasing. Unfortunately, long-term cancer survivors are at increased risk for late effects related to cancer treatment, including ionizing radiation (IR)- and chemotherapy-induced long-term bone marrow (LT-BM) injury. LT-BM injury is primarily attributed to selective induction of oxidative stress and senescence in hematopoietic stem cells (HSCs). The goals of this project are to use our well characterized LT-BM injury mouse models induced by total body irradiation (TBI) or chemotherapy to (1) identify the primary cellular origins of reactive oxygen species (ROS) in HSCs, (2) elucidate how production of ROS in HSCs is regulated, and (3) develop a mechanism-based strategy that can effectively inhibit IR- and chemotherapy-induced HSC senescence and LT-BM suppression via selective inhibition of ROS production in HSCs. Specifically, the hypotheses to be tested are that (1) ROS derived from NADPH oxidase 4 (NOX4) is primarily responsible for mediating IR- and chemotherapy-induced HSC senescence and (2) inhibition of NOX4 can be developed as a novel therapeutic strategy to effectively reduce IR- and chemotherapy-induced LT-BM injury. Three specific aims will be pursued to test these hypotheses. Aim 1: Determine whether NOX4 is primarily responsible for the production of ROS in HSCs to mediate TBI-induced HSC senescence and LT-BM injury. Aim 2: Investigate whether activation of the mammalian target of rapamycin (mTOR)-hypoxia-inducible factor 1 (HIF1) pathway mediates IR-induced upregulation of NOX4 in HSCs. Aim 3: Determine whether inhibition of NOX4 activity with a NOX inhibitor or suppression of NOX4 upregulation with an mTOR inhibitor can effectively inhibit HSC senescence and LT-BM injury induced by not only IR but also chemotherapy. These proposed studies will gain fundamental insights into the pathogenesis of LT-BM injury induced by IR and chemotherapy. These insights will aid in the development of more effective strategies to prevent and mitigate IR- and chemotherapy-induced LT-BM toxicity. Because increased expression of NOX4 and aberrant activation of mTOR are involved in tumorigenesis and tumor resistance to therapy, targeted inhibition of NOX4 or mTOR may provide cancer patients the dual benefits of reducing IR- and chemotherapy-induced LT-BM suppression while increasing tumor response to cancer therapy.