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: 8628818
• 负责人: DENNIS E HALLAHAN
• 金额: $ 44.16万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628818
• 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; Genome; Goals; 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; histone modification; improved; in vivo; inhibitor/antagonist; insight; intestinal crypt; irradiation; loss of function; mouse model; nerve stem cell; novel; overexpression; prevent; public health relevance; 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(申请人提供)：放射治疗是治疗癌症的一种有效方法，尽管结果往往各不相同。非常清楚的是，细胞在它们的 对电离辐射引起的DNA损伤的反应取决于其细胞类型、分化状态、增殖状态和细胞周期阶段等。正常干细胞表现出辐射敏感的表型，导致放射治疗后正常组织损伤的急性和慢性后遗症，但分化后的细胞表现出凋亡功能的丧失和辐射抵抗。大多数研究主要集中在肿瘤的放射增敏方面，而对正常组织的辐射防护方面的研究较少。因此，更好地了解不同细胞环境下的不同辐射反应对于通过放射治疗有效地治疗和管理恶性肿瘤是必要的。细胞对DNA损伤的反应依赖于复杂而复杂的DNA损伤反应信号网络的组合，这些网络监控/维持基因组的完整性，以及消除受损细胞的细胞死亡信号通路。本研究的目的是研究磷酸化蛋白磷酸酶-2A(PP2A)在正常干细胞辐射敏感性调节中的作用。具体地说，已经提出了一种多方面的方法来揭示细胞分化、DNA损伤反应和凋亡反应之间的新关联。利用体内正常干细胞组织生态位，以及正常干细胞和分化细胞的等基因原代培养模型，将阐明干细胞辐射敏感性的分子基础以及PP2A在抑制DNA损伤反应和促进正常干细胞凋亡反应中的双重作用，并确定PP2A的有效性是开发新型辐射防护药物的分子靶点。这种对干细胞独特的不同于分化的后代细胞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至关重要，以有效地减少与放射治疗的不良副作用相关的干细胞丢失，这种副作用损害了癌症幸存者的生活质量，特别是在儿童肿瘤中。