Radiation-induced gastrointestinal syndrome (RIGS) results from a combination of direct cytocidal effects on intestinal crypt and endothelial cells and subsequent loss of the mucosal barrier, resulting in microbial infection, septic shock and systemic infiammatory response syndrome. Currentiy, there is no therapy for RIGS. Irradiation induces apoptosis of crypt endothelial cells, intestinal stem cells (ISC) and enterocytes within hours. We rationalized that the acute loss of cells in situ requires rapid compensation of their functions and this was best achieved with cell replacement therapies, e.g., blood transfusion for hemorrhage. The stroma of solid organs contains a variety of supporting cells, such as, mesenchymal and microvascular endothelial cells, macrophages and lymphocytes. These stromal cells provide the niche and could supply critical growth factor/signals for ISC regeneration. For example, upon intestinal mucosal disruption, resident macrophages in the intestinal submocosal layers are activated by pathogen-derived ligands for Toll-like receptors (TLR) and transmit regenerative signals to ISCs. We thereby propose intestinal regenerative therapy with a combination of systemic administration of growth factors and cell replacement therapy to salvage Gl function post-radiation exposure. In order to develop an stem cell-based therapeutic strategy for RIGS, we hypothesized that combinations of: a) intestinal stem cell growth factor, R-spondinl (R-spol), b) TLR ligands, and c) transplantation of bone marrow-derived endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) would restore the IR-damaged ISC niche, protect against IR-induced cell death and provide growth signals for host ISC regeneration, thus providing protection and mitigation from RIGS.
Aim I Pathophysiologic Mechanisms, Discovery and Validation of Molecular Targets in RIGS Aim II will investigate whether acceleration of ISC regeneration could mitigate/protect RIGS by administration of a Wnt agonist, R-spondinl and a BMP antagonist.
Aim III will examine whether repair of the ISC niche by TLR activation and/or bone marrow-derived adherent stromal cell-based therapies could mitigate RIGS in mice. The final goal is to identify radio-mitigating factors secreted by stromal cells.
Cell based therapies raise hope as transplantation of bone marrow stromal cells mitigate RIGS, 24 hrs after exposure to 18 Gy whole abdominal irradiation. Ideal therapy for RIGS would be multimodal that stimulates ISC regeneration (R-spondinl) and restores the Gl mucosal integrity;provides supportive therapy to prevent infection and dehydration;and induces repopulation ofthe intestinal and mesenchymal stem cells.
|Nie, Wenna; Yan, Leyu; Lee, Yie H et al. (2016) Advanced mass spectrometry-based multi-omics technologies for exploring the pathogenesis of hepatocellular carcinoma. Mass Spectrom Rev 35:331-49|
|Kulkarni, Shilpa; Koller, Antonius; Mani, Kartik M et al. (2016) Identifying Urinary and Serum Exosome Biomarkers for Radiation Exposure Using a Data Dependent Acquisition and SWATH-MS Combined Workflow. Int J Radiat Oncol Biol Phys 96:566-77|
|Brodin, N Patrik; Chen, Yong; Yaparpalvi, Ravindra et al. (2016) Dosimetry Formalism and Implementation of a Homogenous Irradiation Protocol to Improve the Accuracy of Small Animal Whole-Body Irradiation Using a 137Cs Irradiator. Health Phys 110:S26-38|
|Qiu, Yunping; Moir, Robyn; Willis, Ian et al. (2016) Isotopic Ratio Outlier Analysis of the S. cerevisiae Metabolome Using Accurate Mass Gas Chromatography/Time-of-Flight Mass Spectrometry: A New Method for Discovery. Anal Chem 88:2747-54|
|Saha, Subhrajit; Aranda, Evelyn; Hayakawa, Yoku et al. (2016) Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nat Commun 7:13096|
|Goldman, Devorah C; Alexeev, Vitali; Lash, Elizabeth et al. (2015) The triterpenoid RTA 408 is a robust mitigator of hematopoietic acute radiation syndrome in mice. Radiat Res 183:338-44|
|Acharya, Sanket S; Fendler, Wojciech; Watson, Jacqueline et al. (2015) Serum microRNAs are early indicators of survival after radiation-induced hematopoietic injury. Sci Transl Med 7:287ra69|
|Landis, Charles S; Zhou, Hongchao; Liu, Laibin et al. (2015) Liver regeneration and energetic changes in rats following hepatic radiation therapy and hepatocyte transplantation by Â³Â¹P MRSI. Liver Int 35:1145-51|
|Kurland, Irwin Jack; Broin, Pilib Ã“; Golden, Aaron et al. (2015) Integrative Metabolic Signatures for Hepatic Radiation Injury. PLoS One 10:e0124795|
|Ã“ Broin, Pilib; Vaitheesvaran, Bhavapriya; Saha, Subhrajit et al. (2015) Intestinal microbiota-derived metabolomic blood plasma markers for prior radiation injury. Int J Radiat Oncol Biol Phys 91:360-7|
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