Identification of ACE2 as an early tissue-specific biomarker of GI-ARS using a dual specimen strategy - Project summary/Abstract Title: Identification of ACE2 as an early tissue-specific biomarker of GI-ARS using a dual specimen strategy The project aims to develop a novel, dual-specimen biomarker strategy to improve the early detection of gastrointestinal acute radiation syndrome (GI-ARS), a critical condition that arises from ionizing radiation (IR) exposure. IR exposure can lead to both hematopoietic (H-ARS) and GI-ARS, but GI-ARS typically manifests earlier, requiring prompt diagnosis and intervention to improve survival outcomes. Existing GI-ARS biomarkers, such as serum citrulline, are effective only after the initial 48-hour window post-exposure, limiting their utility in early clinical interventions. To address this gap, this study will evaluate angiotensin-converting enzyme 2 (ACE2), an enterocyte-specific protein highly responsive to IR, as a promising early biomarker that can be detected within 1–2 days post-exposure. By combining fecal and serum measurements of ACE2, this project proposes a sensitive and minimally invasive biomarker strategy for predicting GI-ARS severity with high accuracy. This study will leverage a dual-specimen approach to provide a more comprehensive measure of GI injury, capturing both tissue-specific and systemic GI injury responses to IR. Aim 1: will evaluate the temporal dynamics and dose-dependent changes in fecal and serum ACE2 following IR exposure for early GI-ARS prediction. Using total-body irradiated (TBI) mouse models, we will monitor ACE2 levels over the critical 1 to 3.5 days post-IR period, hypothesizing that IR will induce a dose-dependent increase in fecal ACE2 (indicating enterocyte shedding) and a corresponding decrease in serum ACE2 (signaling systemic GI injury). This dual- specimen strategy is expected to yield a more precise GI-ARS prediction within the first 24–48 hours post- exposure compared to current markers. Aim 2: will evaluate the predictive value of fecal-to-serum ACE2 ratio- based biomarkers for early detection and severity of GI-ARS. Using both TBI and total abdominal irradiation (TAI) models, we will validate the fecal-to-serum ACE2 ratio's ability to reliably indicate GI-ARS severity. We will further explore whether the fecal ACE2-to-serum citrulline ratio could provide an alternative predictive metric, especially valuable for mitigating the variability often present in single biomarker models. This study introduces a dual-specimen ACE2 biomarker strategy that addresses the urgent need for early GI-ARS detection. By measuring ACE2 in both fecal and serum samples, we offer a minimally invasive approach that allows for localized (fecal) and systemic (serum) assessment of IR-induced GI injury. The fecal-to-serum ACE2 ratio may improve diagnostic accuracy, surpassing traditional biomarkers such as serum citrulline, particularly at early time points. This approach is transformative in scenarios of nuclear exposure or mass casualties, where rapid and reliable GI injury assessment is critical. The study's findings could enable swift clinical translation, enhancing survival outcomes through timely diagnosis and management of IR-induced GI injuries. 1
