THE ROLE OF PROTEIN PHOSPHATASE PP2A IN RADIATION INDUCED STEM CELL APOPTOSIS

蛋白磷酸酶 PP2A 在辐射诱导干细胞凋亡中的作用

• 批准号: 8828607
• 负责人: DENNIS E HALLAHAN
• 金额: $ 45.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828607
• 关键词: ATM activation; Acute; Adverse effects; Apoptosis; Apoptotic; Attenuated; Biological; Biological Assay; Body Weight decreased; Brain; Cancer Survivor; Caspase; Catalytic Domain; Cell Cycle Stage; Cell Death; Cell Death Signaling Process; Cell Survival; Cells; Chronic; Clear Cell; Clinical; Colony-Forming Units Assay; Comet Assay; Complex; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Development; Dose; Double Strand Break Repair; Dropout; Drops; Exhibits; Genes; Goals; Health; Impairment; In Situ Nick-End Labeling; Induction of Apoptosis; Injury; Intervention; Intestines; Ionizing radiation; Learning; Life; Low Dose Radiation; Malignant Neoplasms; Methods; Modeling; Molecular; Molecular Target; Monitor; Normal tissue morphology; Nuclear Translocation; Organ; Outcome; Pathway interactions; Pediatric Neoplasm; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Prevention strategy; Primary Cell Cultures; Protein Dephosphorylation; Protein phosphatase; Proteins; Quality of life; RNA Interference; Radiation; Radiation Induced DNA Damage; Radiation Injuries; Radiation Tolerance; Radiation therapy; Radiation-Protective Agents; Radioprotection; Radiosensitization; Regulation; Regulator Genes; Research; Role; Signal Pathway; Signal Transduction; Skin; Stem cells; Testing; Testis; Therapeutic; Tissues; Undifferentiated; Ventricular; attenuation; base; cancer cell; caspase-3; cell injury; cell type; cellular imaging; epigenomics; genome integrity; histone modification; improved; in vivo; inhibitor/antagonist; insight; intestinal crypt; irradiation; loss of function; mouse model; nerve stem cell; novel; overexpression; prevent; radiation response; radiation-induced injury; radioresistant; radiosensitive; repaired; response; stem; stem cell niche; tumor

DESCRIPTION (provided by applicant): Radiotherapy is an efficient method of treating cancers albeit often resulting in varying outcomes. It is abundantly clear that cells vary in their response to ionizing radiation induced DNA damage depending on their cell type, differentiation status, proliferation state and cell cycle stage etc. Normal stem cells exhibit a radiosensitive phenotype contributing to acute and chronic sequelae of normal tissue injury following radiotherapy, but differentiated cells display a loss of function of apoptosis and are radioresistant. Most of the research has focused primarily on radiosensitization of tumor and less on radioprotection of normal tissues. Therefore, an improved understanding of differential radiation responses in varying cellular contexts is imperative for efficient treatment and management of malignancies by radiotherapy. Cellular response to DNA damage depends on the combination of complex and sophisticated networks of DNA damage response signals that monitor/ maintain genome integrity and cell death signaling pathways that eliminate damaged cells. The goal of this research is to characterize the role of phospho protein phosphatase- 2A (PP2A) in regulation of radiosensitivity of normal stem cells. Specifically, a multifaceted approach has been proposed to unravel the novel associations between cellular differentiation, DNA damage response and apoptotic response. Utilizing the normal stem cell tissue niches in vivo, as well as isogenic primary cell culture models of normal stem and differentiated cells, molecular basis of stem cell radiosensitivity and the dual role of PP2A in inhibiting DNA damage response and promoting apoptotic response in normal stem cells will be delineated along with determining the validity of PP2A is a molecular target for development of novel radioprotective drugs. This insight into the molecular switches and signal transduction networks unique to stem cells that are different from the differentiated progeny cells would be crucial for developing therapeutic prevention and intervention strategies to effectively minimize the stem cell drop-out associated with undesired side effects of radiotherapy which impairs the quality of life of cancer survivors especially in the pediatric neoplasms.

描述（由申请人提供）：放射疗法是治疗癌症的有效方法，尽管经常导致不同的结果。很明显，细胞在它们的 正常干细胞表现出放射敏感性表型，导致放射治疗后正常组织损伤的急性和慢性后遗症，但分化的细胞表现出凋亡功能丧失，具有放射抗性。目前的研究主要集中在肿瘤的放射增敏方面，而对正常组织的放射防护研究较少。因此，在不同的细胞背景下的差异辐射反应的更好的理解是必要的有效的治疗和管理的恶性肿瘤的放射治疗。细胞对DNA损伤的反应取决于监测/维持基因组完整性的DNA损伤反应信号和消除受损细胞的细胞死亡信号传导途径的复杂和精密网络的组合。本研究的目的是表征磷酸蛋白磷酸酶-2A（PP 2A）在调节正常干细胞辐射敏感性中的作用。具体而言，已经提出了一种多方面的方法来解开细胞分化，DNA损伤反应和凋亡反应之间的新的关联。利用体内正常干细胞的组织微环境，以及正常干细胞和分化细胞的等基因原代培养模型，阐明了干细胞辐射敏感性的分子基础以及PP 2A在抑制正常干细胞DNA损伤反应和促进凋亡反应中的双重作用，沿着确定PP 2A是否是开发新型辐射防护药物的分子靶点。这种对不同于分化后代细胞的干细胞所特有的分子开关和信号转导网络的洞察对于开发治疗预防和干预策略以有效地最小化与放射治疗的不良副作用相关的干细胞脱落是至关重要的，放射治疗的不良副作用损害了癌症幸存者的生活质量，特别是在儿科肿瘤中。