Task DNA Damage Responses Induced by HZE Particles In Human Cells (Completed)
Last Published:  11/23/20 11:55:12 AM (Central)
Short Title: HZE DNA
Responsible HRP Element: Space Radiation
Collaborating Org(s):
Funding Status: Completed - Task completed and produced a deliverable
Procurement Mechanism(s):
Solicited
Aims:
  1. To test the hypothesis that HZE particles may induce a different gene expression profile than that induced by low LET radiation.
    1. To determine global gene expression patterns induced by HZE and X-rays at a dose of equal survival level. Metabolic pathways and expression markers specific to HZE responses in normal human fibroblasts will be identified. Especially, we will focus on pathways/gene groups related to cell proliferation, stress responses, DNA repair and protein kinases.
    2. To determine whether gene expression profiles induced by HZE will vary as a function of energy of the HZE particles.
    3. To determine whether transfer of media from HZE-irradiated cells to non-irradiated cells would induce specific gene expression changes in the recipient cells.
  2. To verify the hypothesis that DNA double-strand breaks induced by HZE particles are persistently unrejoined in normal human fibroblasts.
    1. To determine the RBE of gamma-H2AX phosphorylation and focus formation by HZE and X-rays at equal survival doses in normal human fibroblasts.
    2. To determine whether gamma-H2AX phosphorylation is significantly more persistent at the sites of HZE-induced DSBs as compared to X-rays.
    3. To determine whether the induction and persistence of H2AX phosphorylation and focus formation will vary as a function of energy of the HZE particles.
  3. To test the hypothesis that HZE particles would induce a persistent and/or altered molecular and cellular response than that induced by X-rays in mammalian cells.
    1. To determine whether key DNA DSB-sensing protein kinases, DNA-dependent protein kinase (DNA-PKcs) and ataxia telangiectasia mutated (ATM), are persistently phosphorylated and activated upon HZE exposure in human fibroblasts.
    2. To determine whether the key DSB-signaling and damage-induced cell cycle check point proteins (the MRN complex, MDC1, SMC1, Chk1, Chk2, and p53) are persistently localized on DNA damage sites and/or phosphorylated upon HZE particle exposure in human fibroblasts.
    3. To determine if the interaction between homologous recombination (HR) and nonhomologous end joining (NHEJ) proteins with DNA lesions induced by HZE is different from that observed with X-rays.
  4. To test the hypothesis that high HZE may generate factors that induce a bystander effect or bystander-like effect.
    1. To determine the extent of DSB induction mediated by bystander and bystander-like effects in HZE-irradiated cells, as measured by H2AX phosphorylation and focus formation and localization of DSB sensing and signaling proteins.
    2. To determine whether bystander effects and bystander-like effects are mediated by ROS or modulated through lipid peroxidation in HZE-particle irradiated cells.
    3. To determine whether DSB repair capability (HR and/or NHEJ) plays a role in modulating HZE particles-induced bystander and bystander-like effects in mammalian cells.
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