Radiation-induced heart disease (RIHD) is a potentially severe side effect of radiotherapy of thoracic and chest wall tumors. Despite advances in radiation delivery and treatment planning technology, cardiac radiation toxicity remains a key consideration in thoracic radiotherapy. Hence, research is urgently needed to elucidate biological mechanisms and identify potential targets for intervention. Our previous pre-clinical studies in a mast cell-deficient rat model have shown that, contrary to what had been the prevailing assumption, mast cells play a predominantly protective role in RIHD. The overall goal of this project is to uncover the role of three mast cell targets in RIHD. For this purpose, genetic animal models and pharmacological interventions will be used to define the involvement of 1) Proteinase-Activated Receptor (PAR)-2, the receptor that mediates cellular effects of mast cell proteinases;2) bradykinin, a cardioprotective hormone that is formed by mast cell proteinases;and 3) the cardioprotective sensory neuropeptide calcitonin gene-related peptide (CGRP), as part of the neuroimmune interactions that are known to alter cardiac function and disease. Functional, structural, cellular and molecular manifestations of RIHD will be measured after local heart irradiation. These in vivo experiments will be the first to provide mechanistic insight into the protective effects of mast cells in RIHD, providing critical pre-clinical data as a basis for future development of intervention strategies, thereby enhancing the efficacy and safety of thoracic radiotherapy.

Public Health Relevance

Radiation-induced heart disease (RIHD) is a severe side effect of radiotherapy of thoracic and chest wall tumors. This project will investigate underlying mechanisms of RIHD and will provide critical pre-clinical data as a basis for future development of strategies aimed at reducing RIHD, thereby enhancing the efficacy and safety of thoracic radiotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148679-03
Application #
8256609
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Prasanna, Pat G
Project Start
2010-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$291,849
Indirect Cost
$90,574
Name
University of Arkansas for Medical Sciences
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Sridharan, Vijayalakshmi; Seawright, John W; Antonawich, Francis J et al. (2017) Late Administration of a Palladium Lipoic Acid Complex (POLY-MVA) Modifies Cardiac Mitochondria but Not Functional or Structural Manifestations of Radiation-Induced Heart Disease in a Rat Model. Radiat Res 187:361-366
Ramadan, Samy S; Sridharan, Vijayalakshmi; Koturbash, Igor et al. (2016) A priming dose of protons alters the early cardiac cellular and molecular response to (56)Fe irradiation. Life Sci Space Res (Amst) 8:8-13
Koturbash, Igor; Miousse, Isabelle R; Sridharan, Vijayalakshmi et al. (2016) Radiation-induced changes in DNA methylation of repetitive elements in the mouse heart. Mutat Res 787:43-53
Boerma, Marjan; Sridharan, Vijayalakshmi; Mao, Xiao-Wen et al. (2016) Effects of ionizing radiation on the heart. Mutat Res 770:319-327
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Sridharan, Vijayalakshmi; Thomas, Chanice J; Cao, Maohua et al. (2016) Effects of local irradiation combined with sunitinib on early remodeling, mitochondria, and oxidative stress in the rat heart. Radiother Oncol 119:259-64
Lieblong, Benjamin J; Sridharan, Vijayalakshmi; Srivastava, Anup K et al. (2015) Role of the bradykinin B2 receptor in a rat model of local heart irradiation. Int J Radiat Biol 91:634-42
Boerma, Marjan; Singh, Preeti; Sridharan, Vijayalakshmi et al. (2015) Effects of Local Heart Irradiation in a Glutathione S-Transferase Alpha 4-Null Mouse Model. Radiat Res 183:610-9
Pathak, Rupak; Shao, Lijian; Ghosh, Sanchita P et al. (2015) Thrombomodulin contributes to gamma tocotrienol-mediated lethality protection and hematopoietic cell recovery in irradiated mice. PLoS One 10:e0122511

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