Serum pro-N-cadherin as an early biomarker of radiation-induced heart disease - In the scenario of a nuclear accident or radiological attack, the survivors of acute radiation syndrome (ARS) may be at risk of developing Delayed Effects of Acute Radiation Exposure (DEARE), which can lead to severe morbidity and death due to injury of multiple organs such as the heart. Although it has been demonstrated that exposure to ionizing radiation significantly increases the risk of cardiac dysfunction, there is no FDA-approved biomarker that can accurately predict the risk of heart disease among individuals who have been exposed to heterogeneous doses of ionizing radiation from nuclear terrorism. Thus, the overall goal of this U01 grant proposal is to develop an early biomarker that can identify victims of radiological attacks who are at high risk of developing heart disease following radiation exposure and would benefit from early therapeutic intervention. Our published data demonstrate that fibroblasts isolated from the fibrotic heart express N-cadherin on the cell surface in the precursor form as pro-N-cadherin (PNC). In our recent publication, we demonstrate that serum PNC is an early marker of subclinical heart failure in the general population. In addition, our preliminary data show that PNC+ cells are substantially enriched in the heart of various animal models of cardiac injury including cardiac transplant rejection and ionizing radiation. We hypothesize that radiation damage to the heart promotes tissue remodeling and aberrant cell-surface PNC localization in cardiac fibroblasts. Thus, serum PNC will be a promising biomarker to predict the risk of heart disease after radiation exposure among survivors of ARS. We will test this hypothesis by using serum samples from non-human primates that survived ARS and cancer patients treated with radiation therapy for breast cancer, esophageal cancer, or lung cancer. In addition, we will conduct mechanistic studies in vivo and in vitro to define the population of cardiac fibroblasts expressing PNC+ and mechanisms of aberrant cell-surface PNC localization in the irradiated heart of mice. We anticipate that by completing the proposed experiments, we will generate critical data to support the further development of serum PNC as an early biomarker for predicting the risk of heart disease among individuals affected by accidental radiation exposure through the FDA animal rule.
