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Title: Integrative Radiation Biology

Abstract

We plan to study tissue-level mechanisms important to human breast radiation carcinogenesis. We propose that the cell biology of irradiated tissues reveals a coordinated multicellular damage response program in which individual cell contributions are primarily directed towards suppression of carcinogenesis and reestablishment of homeostasis. We identified transforming growth factor β1 (TGFβ) as a pivotal signal. Notably, we have discovered that TGFβ suppresses genomic instability by controlling the intrinsic DNA damage response and centrosome integrity. However, TGFβ also mediates disruption of microenvironment interactions, which drive epithelial to mesenchymal transition in irradiated human mammary epithelial cells. This apparent paradox of positive and negative controls by TGFβ is the topic of the present proposal. First, we postulate that these phenotypes manifest differentially following fractionated or chronic exposures; second, that the interactions of multiple cell types in tissues modify the responses evident in this single cell type culture models. The goals are to: 1) study the effect of low dose rate and fractionated radiation exposure in combination with TGFβ on the irradiated phenotype and genomic instability of non-malignant human epithelial cells; and 2) determine whether stromal-epithelial interactions suppress the irradiated phenotype in cell culture and the humanized mammary mouse model. These data will bemore » used to 3) develop a systems biology model that integrates radiation effects across multiple levels of tissue organization and time. Modeling multicellular radiation responses coordinated via extracellular signaling could have a significant impact on the extrapolation of human health risks from high dose to low dose/rate radiation exposure.« less

Authors:
 [1]
  1. New York University School of Medicine, NY (United States)
Publication Date:
Research Org.:
New York University School of Medicine, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1171380
Report Number(s):
DOE-NYUSOM64654
DOE Contract Number:
FG02-08ER64654
Resource Type:
Technical Report
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; radiation; radiobiology; cancer; carcinogenesis; DNA; breast; breast cancer; tumor; microtumor; TGG-beta

Citation Formats

Barcellos-Hoff, Mary Helen. Integrative Radiation Biology. United States: N. p., 2015. Web. doi:10.2172/1171380.
Barcellos-Hoff, Mary Helen. Integrative Radiation Biology. United States. doi:10.2172/1171380.
Barcellos-Hoff, Mary Helen. 2015. "Integrative Radiation Biology". United States. doi:10.2172/1171380. https://www.osti.gov/servlets/purl/1171380.
@article{osti_1171380,
title = {Integrative Radiation Biology},
author = {Barcellos-Hoff, Mary Helen},
abstractNote = {We plan to study tissue-level mechanisms important to human breast radiation carcinogenesis. We propose that the cell biology of irradiated tissues reveals a coordinated multicellular damage response program in which individual cell contributions are primarily directed towards suppression of carcinogenesis and reestablishment of homeostasis. We identified transforming growth factor β1 (TGFβ) as a pivotal signal. Notably, we have discovered that TGFβ suppresses genomic instability by controlling the intrinsic DNA damage response and centrosome integrity. However, TGFβ also mediates disruption of microenvironment interactions, which drive epithelial to mesenchymal transition in irradiated human mammary epithelial cells. This apparent paradox of positive and negative controls by TGFβ is the topic of the present proposal. First, we postulate that these phenotypes manifest differentially following fractionated or chronic exposures; second, that the interactions of multiple cell types in tissues modify the responses evident in this single cell type culture models. The goals are to: 1) study the effect of low dose rate and fractionated radiation exposure in combination with TGFβ on the irradiated phenotype and genomic instability of non-malignant human epithelial cells; and 2) determine whether stromal-epithelial interactions suppress the irradiated phenotype in cell culture and the humanized mammary mouse model. These data will be used to 3) develop a systems biology model that integrates radiation effects across multiple levels of tissue organization and time. Modeling multicellular radiation responses coordinated via extracellular signaling could have a significant impact on the extrapolation of human health risks from high dose to low dose/rate radiation exposure.},
doi = {10.2172/1171380},
journal = {},
number = ,
volume = ,
place = {United States},
year = 2015,
month = 2
}

Technical Report:

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