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.
Radiation-induced injury to normal tissues impairs the quality of life of cancer survivors, especially following radiation therapy for childhood neoplasms. Low dose radiation-induced apoptosis occurs selectively in stem cells which display an attenuated DNA damage response and rapid induction of apoptosis following irradiation. Goal of the proposed research is to characterize the molecular basis of stem cell radiosensitivity and to characterize the efficacy of PP2A phosphatase as a novel molecular target for development of radioprotective drugs.
|Fabbrizi, Maria Rita; Meyer, Barbara; Misri, Sandeep et al. (2018) Transient PP2A inhibition alleviates normal tissue stem cell susceptibility to cell death during radiotherapy. Cell Death Dis 9:492|
|Meyer, Barbara; Fabbrizi, Maria Rita; Raj, Suyash et al. (2016) Histone H3 Lysine 9 Acetylation Obstructs ATM Activation and Promotes Ionizing Radiation Sensitivity in Normal Stem Cells. Stem Cell Reports 7:1013-1022|
|Dadey, David Y A; Kapoor, Vaishali; Khudanyan, Arpine et al. (2016) The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma. Oncotarget 7:2080-92|
|Jacobs, Keith M; Misri, Sandeep; Meyer, Barbara et al. (2016) Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses. Mol Biol Cell 27:1332-45|
|Kaliberov, S A; Kaliberova, L N; Yan, H et al. (2016) Retargeted adenoviruses for radiation-guided gene delivery. Cancer Gene Ther 23:303-14|
|Zhao, Diana Yi; Jacobs, Keith M; Hallahan, Dennis E et al. (2015) Silencing Egr1 Attenuates Radiation-Induced Apoptosis in Normal Tissues while Killing Cancer Cells and Delaying Tumor Growth. Mol Cancer Ther 14:2343-52|
|Jiang, Xiaoyu; Yuan, Liya; Engelbach, John A et al. (2015) A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis. PLoS One 10:e0139596|
|Jiang, Xiaoyu; Engelbach, John A; Yuan, Liya et al. (2014) Anti-VEGF antibodies mitigate the development of radiation necrosis in mouse brain. Clin Cancer Res 20:2695-702|