title: Proteomic Profiling of Hematopoietic Stem/Progenitor Cells after a Whole Body Exposure of CBA/CaJ Mice to Titanium (48Ti) Ions.
abstract: Myeloid leukemia (ML) is one of the major health concerns from exposure to radiation. However, the risk assessment for developing ML after exposure to space radiation remains uncertain. To reduce the uncertainty in risk prediction for ML, a much increased understanding of space radiation-induced changes in the target cells,i.e., hematopoietic stem/progenitor cells (HSPCs), is critically important. We used the label-free quantitative mass spectrometry (LFQMS) proteomic approach to determine the expression of protein in HSPC-derived myeloid colonies obtained at an early time-point (one week) and a late time-point (six months) after an acute whole body exposure of CBA/CaJ mice to a total dose of 0, 0.1, 0.25, or 0.5 Gy of heavy-ion titanium (48Ti ions), which are the important component of radiation found in the space environment. Mice exposed to 0 Gy of48Ti ions served as non-irradiated sham controls. There were five mice per treatment groups at each harvest time. The Trans-Proteomic Pipeline (TPP) was used to assign a probability of a particular protein being in the sample. A proof-of-concept based Ingenuity Pathway Analysis (IPA) was used to characterize the functions, pathways, and networks of the identified proteins. Alterations of expression levels of proteins detected in samples collected at one week (wk) post-irradiation reflects acute effects of exposure to48Ti ions, while those detected in samples collected at six months (mos) post-irradiation represent protein expression profiles involved in the induction of late-occurring damage (normally referred to as genomic instability). Our results obtained by using the IPA analyses indicate a wide array of signaling pathways involved in response to 1 GeV/n48Ti ions at both harvest times. Our data also demonstrate that the patterns of protein expression profiles are dose and time dependent. The majority of proteins with altered expression levels are involved in cell cycle control, cellular growth and proliferation, cell death and survival, cell-to-cell signaling and interaction. The IPA analyses indicate several important processes involved in responses to exposure to48Ti ions. These include the proteosme/ubiquination, protein synthesis, post-translation modification, and lipid metabolism. The IPA analyses also indicate that exposure to 1 GeV/n48Ti ions affects the development and function of hematological system, immune cell trafficking, including the cytoskeleton. Further, the IPA analyses strongly demonstrate that the NF-κB and MAPKs (ERKs, JNKs, and p38MAPK) pathways play an essential role in signal transduction after exposure to 1 GeV/n48Ti ions. At an early time-point (1 week), the top networks identified by the IPA analyses are related to metabolic disease, lipid metabolism, small molecule biochemistry, and development disorder. In contrast, the top networks identified in samples collected at a late time-point (6 mos post-irradiation) by the IPA analyses are related to cancer, hematological disorders, and immunological diseases. In summary, the proteomic findings from our study provide a foundation to uncover compounds potentially be highly effective in radiation countermeasures.
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. kanokporn.rithidech@stonybrookmedicine.edu.
authors.forename: Kanokporn Noy
authors.initials: KN
authors.lastname: Rithidech
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. mtungjai@gmail.com.|Department of Radiologic Technology, Faculty of Associated Medical Sciences, Center of Excellence for Molecular Imaging, Chiang Mai University, Chiang Mai 50200, Thailand. mtungjai@gmail.com.
authors.forename: Montree
authors.initials: M
authors.lastname: Tungjai
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. witawat.jangiam@stonybrookmedicine.edu.|Department of Chemical Engineering, Burapha University, Chonburi 20131, Thailand. witawat.jangiam@stonybrookmedicine.edu.
authors.forename: Witawat
authors.initials: W
authors.lastname: Jangiam
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. lmhonikel@hotmail.com.
authors.forename: Louise
authors.initials: L
authors.lastname: Honikel
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. chris.gordon@stonybrookmedicine.edu.
authors.forename: Chris
authors.initials: C
authors.lastname: Gordon
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Room 0044, Indianapolis, IN 46202, USA. xlai@iu.edu.
authors.forename: Xianyin
authors.initials: X
authors.lastname: Lai
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Room 362A, Indianapolis, IN 46202, USA. fwitzmann@iupui.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Witzmann
keywords: hematopoietic stem/progenitor cells; mice; proteomics; space radiation