Methods of determining levels of exposure to radiation and uses thereof

Abstract

Provided herein are methods of determining a subject's level of exposure to radiation and methods of determining a subject's risk of subsequent development of radiation disease or risk of poor prognosis from radiation exposure that include determining a level of one or more miRNAs selected from the group consisting of mouse and human homologues of mouse miR-130a-3p, miR-150-5p, miR-17-3p, miR-187-3p, miR-194-5p, miR-27a-3p, miR-30a-3p, miR-30c-5p, miR-142-5p, miR-342-3p, miR-34b-3p, miR-126-3p, miR-320-3p, miR-136-5p, miR-33-5p, miR-142a-3p, miR-706, miR-375-3p, miR-29a-5p, miR-193a-3p, miR-99b-5p, miR-151-3p, miR-let-7d-3p, miR-486-5p, miR-423-5p, miR-30b-5p, miR-191-5p, miR-497a-5p, miR-32-5p, miR-214-5p, miR-326-3p, miR-1195, miR-122-5p, miR-1839-3p, miR-500-3p, miR-30e-3p, miR-322-3p, miR-709, miR-486-3p, miR-133a-3p, miR-676-3p, miR-744-5p, miR-29a-3p, miR-1839-5p, miR-30a-5p, miR-199b-5p, miR-125a-5p, miR-133b-3p, miR-24-3p, miR-21a-5p, miR-503-5p, miR-328-3p, miR-let-7g-5p, miR-362-3p, miR-199a-5p, miR-15a-3p, miR-139-5p, miR-149-5p, miR-29b-3p, miR-1a-3p, miR-23b-3p, miR-215-5p, miR-204-5p, miR-200b-5p, miR-25-3p, miR-338-3p, and miR-196b-5p, in a sample including a biological fluid from the subject.

1 .- 59 . (canceled) 
     
     
         60 . A method of determining the efficacy of a treatment for reducing radiation-induced damage administered to a human subject exposed to a significant dose of radiation, the method comprising:
 (a) determining a first level of one or more miRNAs in a first serum sample obtained from the human subject exposed to a significant dose radiation at a first time point, wherein the one or more miRNAs is selected from the group consisting of miR-130a-3p, miR-150-5p, miR-142-5p, miR-706, miR-342-3p, miR-136-5p, miR-17-3p, miR-126-3p, miR-322-3p, miR-34b-3p, miR-187-3p, miR-194-5p, miR-27a-3p, miR-30a-3p, and miR-30c-5p;   (b) after the first time point and before a second time point, administering the treatment for reducing radiation-induced damage to the human subject;   (c) determining a second level of the one or more miRNAs of step (a) in a second serum sample obtained from the human subject at the second time point; and   (d) determining the efficacy of the treatment for reducing radiation-induced damage administered to the human subject based on a comparison of the second level(s) of the one or more miRNAs to the first level(s) of the one or more miRNAs,   wherein one or more of (i) an elevation in the second level of one or more of miR-136-5p, miR-322-3p, miR-142-5p, miR-706, miR-150-5p, miR-342-3p, miR-17-3p, miR-187-3p, miR-194-5p, and miR-27a-3p, and (ii) a decrease in the second level of one or more of miR-130a-3p, miR-126-3p, miR-34b6-3p, miR-30a-3p, and miR-30c-5p, as compared to the first level(s) of one or more of miR-136-5p, miR-322-3p, miR-142-5p, miR-706, miR-150-5p, miR-342-3p, miR-187-3p, miR-187-3p, miR-194-5p, miR-27a-3p, miR-130a-3p, miR-126-3p, miR-34b-3p, miR-30a-3p, and miR-30c-5p, indicates that the treatment for reducing radiation-induced damage administered to the human subject was effective.   
     
     
         61 .- 64 . (canceled) 
     
     
         65 . The method of  claim 60 , wherein the treatment for reducing radiation-induced damage is selected from the group consisting of: cytokines, potassium iodide, Prussian blue, diethylenetriamine pentaacetic acid, bone marrow transplantation, blood transfusion, and surgery to remove damaged tissues. 
     
     
         66 . The method of  claim 65 , wherein the cytokines are selected from the group consisting of granulocyte colony-stimulating factor, filgrastim, and pegfilgrastim. 
     
     
         67 . The method of  claim 60 , wherein the first and second level(s) of the one or more miRNAs in the first and second serum samples are determined in steps (a) and (c) by amplifying the miRNAs present in the first and second serum samples to generate amplification products, contacting the amplified products to a substrate, and detecting the amplified products bound to the substrate. 
     
     
         68 .- 80 . (canceled) 
     
     
         81 . The method of  claim 60 , wherein the method further comprises administering an alternate treatment to the human subject when the treatment for reducing radiation-induced damage is determined as not being effective. 
     
     
         82 . The method of  claim 60 , wherein the method further comprises administering one or more additional doses of the treatment for reducing radiation-induced damage when the treatment for reducing radiation-induced damage is determined as being effective. 
     
     
         83 . A method of treating a human subject in need thereof, the method comprising:
 (a) determining a level of one or more miRNAs selected from the group consisting of miR-130a-3p, miR-150-5p, miR-142-5p, miR-706, miR-342-3p, miR-17-3p, miR-126-3p, miR-322-3p, miR-136-5p, miR-34b-3p, miR-187-3p, miR-194-5p, miR-27a-3p, miR-30a-3p, and miR-30c-5p in a serum sample from the human subject, wherein the serum sample is obtained from the human subject after a possible exposure of the human subject to radiation;   (b) comparing the level(s) of the one or more miRNAs in the serum sample from the human subject to reference level(s) of the one or more miRNAs, wherein the reference level(s) of the one or more miRNAs are levels of the one or more miRNAs in a reference serum sample from a human subject not exposed to radiation;   (c) determining that
 (i) the human subject's exposure to radiation is sublethal when the level of miR-130a-3p is increased, or the level of miR-142-5p, miR-706, miR-150-5p, or miR-342-3p is decreased in the serum sample from the human subject compared to the reference level(s) of the one or more miRNAs; 
 (ii) the human subject's exposure to radiation is high and not lethal when the level of miR-34b-3p, miR-126-3p, miR-322-3p, or miR-136-5p is increased or the level of miR-17-3p is decreased in the serum sample from the human subject compared to the reference level(s) of the one or more miRNAs; or 
 (iii) the human subject's exposure to radiation is lethal when the level of miR-30a-3p or miR-30c-3p are increased, or the level of miR-187-3p, miR-194-5p, or miR-27a-3p is decreased in the serum sample compared to the reference level(s) of the one or more miRNAs; 
   (d) selecting for the human subject (1) a treatment for reducing damage induced by a sublethal dose of radiation if the human subject's exposure is determined to be sublethal in step (c), (2) a treatment for reducing damage induced by a high and not lethal dose of radiation if the human subject's exposure is determined to be high and not lethal in step (c), or (3) a treatment for reducing damage induced by a lethal dose of radiation if the human subject's exposure is determined to be lethal in step (c); and   (e) administering the treatment of step (d) to the human subject.   
     
     
         84 . The method of  claim 83 , wherein the treatment is selected from the group consisting of: administration of one or more of a cytokine, potassium iodide, Prussian blue, and diethylenetriamine pentaacetic acid, bone marrow transplantation, blood transfusion, and surgery to remove damaged tissues. 
     
     
         85 . The method of  claim 84 , wherein the cytokine is selected from the group consisting of granulocyte colony-stimulating factor, filgrastim, and pegfilgrastim. 
     
     
         86 . The method of  claim 83 , wherein the serum sample is obtained from the human subject within 30 minutes to 96 hours after the possible exposure of the human subject to radiation. 
     
     
         87 . The method of  claim 83 , wherein the sublethal dose of radiation is less than or equal to 2 Gy of radiation; the high and not lethal dose of radiation is greater than 2 Gy to about 6 Gy; and the lethal dose of radiation is greater than about 6.5 Gy. 
     
     
         88 . A method of treating a human subject in need thereof, wherein the human subject is or has previously been determined to have an increased serum level of miR-130a-3p, miR-126-3p, miR-322-3p, miR-136-5p, miR-34b-3p, or miR-30c-5p or a decreased serum level of miR-142-5p, miR-706, miR-150-5p, miR-342-3p, miR-17-3p, or miR-194-5p relative to a reference level of the miRNA, wherein the reference level of the miRNA is a level of the miRNA in a reference serum sample from a human subject not exposed to radiation, the method comprising administering to the human subject a treatment for radiation disease. 
     
     
         89 . The method of  claim 88 , wherein the treatment for radiation disease is selected from the group consisting of: administration of one or more of a cytokine, potassium iodide, Prussian blue, and diethylenetriamine pentaacetic acid, bone marrow transplantation, blood transfusion, and surgery to remove damaged tissues. 
     
     
         90 . The method of  claim 89 , wherein the cytokine is selected from the group consisting of granulocyte colony-stimulating factor, filgrastim, and pegfilgrastim. 
     
     
         91 . The method of  claim 88 , wherein the serum level of miR-130a-3p, miR-126-3p, miR-322-3p, miR-136-5p, miR-34b-3p, and miR-30c-5p, miR-142-5p, miR-706, miR-150-5p, miR-342-3p, miR-17-3p, or miR-194-5p is from a serum sample obtained from the human subject within 30 minutes to 96 hours after possible exposure of the human subject to radiation. 
     
     
         92 . The method of  claim 88 , wherein the treatment is for radiation disease caused by exposure to a sublethal, high and not lethal, or lethal dose of radiation. 
     
     
         93 . The method of  claim 92 , wherein the sublethal dose of radiation is less than or equal to 2 Gy of radiation; the high and not lethal dose of radiation is greater than 2 Gy to about 6 Gy; and the lethal dose of radiation is greater than about 6.5 Gy. 
     
     
         94 . A method of treating a human subject in need thereof, the method comprising:
 (a) determining a level of one or more miRNAs selected from the group consisting of miR-130a-3p, miR-136-5p, miR-150-5p, miR-142-5p, miR-706, miR-322-3p, miR-342-3p, miR-17-3p, miR-126-3p, miR-34b-3p, miR-194-5p, and miR-30c-5p in a serum sample from the human subject;   (b) comparing the levels of the one or more miRNAs in the serum sample from the human subject to reference levels of the one or more miRNAs, wherein the reference levels of the one or more miRNAs are levels of the one or more miRNAs in a reference serum sample from a human subject not exposed to radiation;   (c) determining that the level of the one or more miRNAs miR-130a-3p, miR-126-3p, miR-34b-3p, and miR-30c-5p is increased and the level of the one or more miRNAs miR-142-5p, miR-706, miR-150-5p, miR-342-3p, miR-17-3p, and miR-194-5p, is decreased in the serum sample from the human subject compared to the reference levels of the one or more miRNAs;   (d) selecting a treatment for reducing damage induced by radiation for the human subject; and   (e) administering the treatment for reducing damage induced by radiation to the human subject.