Public Abstract

DE-SC0025578: Evaluation of the cellular and molecular responses of human skin fibroblasts and neurons derived from iPSCs with varying intrinsic radiosensitivity to low dose radiation

Award Status: Active

Institution: University of Texas Southwestern Medical Center, Dallas, TX
UEI: YZJ6DKPM4W63
DUNS:

Most Recent Award Date: 09/10/2024
Number of Support Periods: 1
PM: Kulkarni, Resham

Current Budget Period: 09/01/2024 - 08/31/2025
Current Project Period: 09/01/2024 - 08/31/2027
PI: Davis, Anthony

Supplement Budget Period: N/A

Public Abstract

Exposure to low-dose ionizing radiation is increasing due to medical procedures (CT scans, X-rays, mammograms), natural sources (radon, radionuclides in soil, cosmic rays), and occupational sources (radiation workers). An average individual receives about 2.4 mGy per year, but this can vary based on occupation and geographic location. The health impact of chronic low-dose radiation exposure remains largely unknown. The response to ionizing radiation (IR) varies among individuals. Studies show that individuals with deleterious mutations in DDR genes exhibit radiosensitivity and increased cancer risk. However, variability in intrinsic radioresponse is also observed in individuals without gross DDR gene defects, suggesting other factors—genetics, epigenetics, metabolic pathways, and subtle DDR perturbations—govern radioresponse. A key question is whether a relationship exists between intrinsic radiosensitivity and the risk of adverse events from low-dose radiation exposure. Conversely, are radioresistant individuals less prone to radiation-induced adverse events? To address these questions, we have collected primary human skin fibroblasts (PHSFs) from diverse individuals to assess genetic diversity in the development of adverse late normal tissue effects following low-dose radiation exposure. This panel includes cells from different sexes, ethnic groups, and ages (childhood to late adulthood), enabling us to explore heterogeneity in the cellular response to low-dose radiation. We hypothesize that intrinsic radioresponse influences the cellular response to low-dose radiation. To test this, we will generate induced pluripotent stem cells (iPSCs) and iPSC-derived neurons from PHSFs to characterize neuronal responses to low-dose radiation, as the brain is at risk from such exposure. We will use transcriptomics, genomics, metabolomics, and proteomics to analyze responses in "radionormal," "radioresistant," and "radiosensitive" cohorts (10 per year) compared to untreated controls. To test our hypothesis, we propose the following Aims. (1) Identify consequential transcriptomic and genomic features of intrinsic radioresponse that are associated with the response to low dose radiation, (2) Identify consequential metabolomics features of intrinsic radioresponse that are associated with the response to low dose radiation, and (3) Assess functional proteomics and examine radiation-induced DNA damage response (DDR), genomic instability, and mutation frequency associated with the response to low dose radiation. Collectively, we believe the data generated during this study will allow the DOE to better model the understanding of an individual’s response to low dose radiation.

Exposure to low-dose ionizing radiation is increasing due to medical procedures (CT scans, X-rays, mammograms), natural sources (radon, radionuclides in soil, cosmic rays), and occupational sources (radiation workers). An average individual receives about 2.4 mGy per year, but this can vary based on occupation and geographic location. The health impact of chronic low-dose radiation exposure remains largely unknown. The response to ionizing radiation (IR) varies among individuals. Studies show that individuals with deleterious mutations in DDR genes exhibit radiosensitivity and increased cancer risk. However, variability in intrinsic radioresponse is also observed in individuals without gross DDR gene defects, suggesting other factors—genetics, epigenetics, metabolic pathways, and subtle DDR perturbations—govern radioresponse. A key question is whether a relationship exists between intrinsic radiosensitivity and the risk of adverse events from low-dose radiation exposure. Conversely, are radioresistant individuals less prone to radiation-induced adverse events? To address these questions, we have collected primary human skin fibroblasts (PHSFs) from diverse individuals to assess genetic diversity in the development of adverse late normal tissue effects following low-dose radiation exposure. This panel includes cells from different sexes, ethnic groups, and ages (childhood to late adulthood), enabling us to explore heterogeneity in the cellular response to low-dose radiation. We hypothesize that intrinsic radioresponse influences the cellular response to low-dose radiation. To test this, we will generate induced pluripotent stem cells (iPSCs) and iPSC-derived neurons from PHSFs to characterize neuronal responses to low-dose radiation, as the brain is at risk from such exposure. We will use transcriptomics, genomics, metabolomics, and proteomics to analyze responses in "radionormal," "radioresistant," and "radiosensitive" cohorts (10 per year) compared to untreated controls. To test our hypothesis, we propose the following Aims. (1) Identify consequential transcriptomic and genomic features of intrinsic radioresponse that are associated with the response to low dose radiation, (2) Identify consequential metabolomics features of intrinsic radioresponse that are associated with the response to low dose radiation, and (3) Assess functional proteomics and examine radiation-induced DNA damage response (DDR), genomic instability, and mutation frequency associated with the response to low dose radiation. Collectively, we believe the data generated during this study will allow the DOE to better model the understanding of an individual’s response to low dose radiation.