Cancer Therapy-induced Long-term Bone Marrow Injury

描述(申请人提供)：由于癌症早期发现和治疗的显著改进，癌症幸存者的数量正在增加。不幸的是，长期癌症幸存者面临着与癌症治疗相关的晚期效应的风险增加，包括 电离辐射(IR)和化疗引起的长期骨髓(LT-BM)损伤。Lt-BM损伤主要归因于选择性地诱导造血干细胞(HSCs)氧化应激和衰老。本项目的目标是利用我们已知的全身照射(TBI)或化疗诱导的LT-BM损伤小鼠模型，(1)确定HSCs中活性氧物种(ROS)的主要细胞来源，(2)阐明HSCs中ROS的产生是如何调节的，以及(3)开发一种基于机制的策略，通过选择性抑制HSCs中ROS的产生，有效地抑制IR和化疗诱导的HSC衰老和LT-BM抑制。具体地说，需要检验的假设是：(1)NADPH氧化酶4(NOX4)产生的ROS主要参与介导IR和化疗诱导的HSC衰老；(2)抑制NOX4可以作为有效减轻IR和化疗诱导的LT-BM损伤的一种新的治疗策略。我们将追求三个具体目标来检验这些假说。目的1：确定NOX4是否在介导脑损伤诱导的HSC衰老和Lt-BM损伤中起主要作用。目的：探讨哺乳动物靶基因雷帕霉素(MTOR)-缺氧诱导因子1(HIF1)通路的激活是否参与IR诱导的HSCs中NOX4的表达上调。目的：确定用NOX抑制剂抑制NOX4活性或用mTOR抑制剂抑制NOX4上调是否能有效地抑制IR和化疗所致的HSC衰老和LT-BM损伤。这些研究将对IR和化疗诱导的LT-BM损伤的发病机制有基础的认识。这些见解将有助于开发更有效的策略来预防和减轻IR和化疗引起的LT-BM毒性。由于NOX4的表达增加和mTOR的异常激活与肿瘤的发生和耐药有关，靶向抑制NOX4或mTOR可能为癌症患者提供双重好处：减少IR和化疗诱导的LT-BM抑制，同时提高肿瘤对癌症治疗的反应。

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.