The threat of 'dirty bombs'and the possibility of the use of improvised nuclear weapons is growing with the changing global socio-political scenario and politically turbulent situation in nuclear warhead capable states. Hence, radiation exposure in terrorist events, industrial accidents or natural disasters (such as the nuclear disaster after the tsunami in Japan) is a current and continuing threat for the future. The most important characteristic of such radiation exposure is the heterogeneity of the dose delivered to different parts of the body, and the prominence of symptoms depends on the magnitude of damage to the organs resulting in complex patho-physiological features. It is well established that clinical symptoms of radiation injury to different organs and tissues can appear days, weeks and months after exposure, and this could lead to a delay in the use of any treatment options. Existing biodosimetry techniques and devices do not predict the severity of injury sustained by specific organs and tissues, and thus do not allow for the prompt organ- and tissue-directed medical treatment that might be provided by any available radiation medical countermeasures. We have recently discovered that a new class of gene expression regulators, microRNA (miRNA), impact the radiation response. miRNAs are small (20-22 nts), extremely stable molecules that are easily recovered and detected in a variety of tissues and body fluids including blood serum. The use of serum miRNA expression pattern as predictive markers for different pathological conditions including external trauma is being explored. Unlike the vast number of mRNAs, there are only ~1400 miRNAs in the human genome, and a modest number of miRNAs may be sufficient to distinguish injury to specific organs or tissue. Therefore we speculated that serum miRNA profiles may serve as effective biomarkers for predicting radiation damage to hematopoietic system and lung. In preliminary studies we used a sub-lethal dose of total body irradiation (TBI) to cause hematopoietic injury in mice and assessed the serum miRNA profile a day and week after injury. Histopathological and cellular analysis revealed that specific serum miRNAs correlated with radiation induced damage to bone marrow and other aspects of the hematopoietic system. Interestingly, the results also suggested that distinct sets of miRNAs may allow us to estimate the time-frame after radiation exposure (that is days versus weeks), and this in itself could be of importance for the treatment of the exposed individual. To assess serum miRNA profile changes with lung injury we used multiple doses of localized radiation to the thoracic region and examined the serum miRNA profile weeks after exposure. There were specific sets of serum miRNAs that corresponded to radiation-induced lung injury in a dose-dependent manner. These results suggest that serum miRNA expression may serve as a novel biomarker for acute and delayed radiation injury to the hematopoietic system and lung. Overall the goal is to build on our preliminary studies and establish miRNA signatures that predict radiation injury to allow for timely and appropriate treatment of radiation victims.
A critical step in the medical management of a nuclear disaster would be to identify and treat individuals who have had radiation-induced injury to organs and tissues without obvious symptoms. Serum microRNAs have emerged as a new class of biomarkers that are sensitive, stable, accessible in a non-invasive procedure and can be measured rapidly. In recent years we have discovered a role for microRNAs in the radiation response and the goal of this grant application is to identify serum microRNAs that may serve as predictive markers for radiation-induced damage to lung and the hematopoietic system.
|Fendler, Wojciech; Malachowska, Beata; Meghani, Khyati et al. (2017) Evolutionarily conserved serum microRNAs predict radiation-induced fatality in nonhuman primates. Sci Transl Med 9:|
|Drané, Pascal; Brault, Marie-Eve; Cui, Gaofeng et al. (2017) TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature 543:211-216|
|Choi, Young Eun; Meghani, Khyati; Brault, Marie-Eve et al. (2016) Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer. Cell Rep 14:429-439|
|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|
|Kushwaha, Deepa; Ramakrishnan, Valya; Ng, Kimberly et al. (2014) A genome-wide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas. Oncotarget 5:4026-39|
|Moskwa, Patryk; Zinn, Pascal O; Choi, Young Eun et al. (2014) A functional screen identifies miRs that induce radioresistance in glioblastomas. Mol Cancer Res 12:1767-78|
|Choi, Young Eun; Pan, Yunfeng; Park, Eunmi et al. (2014) MicroRNAs down-regulate homologous recombination in the G1 phase of cycling cells to maintain genomic stability. Elife 3:e02445|
|Shaltiel, Indra A; Aprelia, Melinda; Saurin, Adrian T et al. (2014) Distinct phosphatases antagonize the p53 response in different phases of the cell cycle. Proc Natl Acad Sci U S A 111:7313-8|
|Lee, Dong-Hyun; Acharya, Sanket S; Kwon, Mijung et al. (2014) Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks. Mol Cell 54:512-25|
|Choi, Young Eun; Battelli, Chiara; Watson, Jacqueline et al. (2014) Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells. Oncotarget 5:2678-87|
Showing the most recent 10 out of 11 publications