title: Characterization of transgenic Gfrp knock-in mice: implications for tetrahydrobiopterin in modulation of normal tissue radiation responses.
abstract: OBJECTIVE
  The free radical scavenger and nitric oxide synthase cofactor, 5,6,7,8-tetrahydrobiopterin (BH4), plays a well-documented role in many disorders associated with oxidative stress, including normal tissue radiation responses. Radiation exposure is associated with decreased BH4 levels, while BH4 supplementation attenuates aspects of radiation toxicity. The endogenous synthesis of BH4 is catalyzed by the enzyme guanosine triphosphate cyclohydrolase I (GTPCH1), which is regulated by the inhibitory GTP cyclohydrolase I feedback regulatory protein (GFRP). We here report and characterize a novel, Cre-Lox-driven, transgenic mouse model that overexpresses Gfrp.
  
  
  RESULTS
  Compared to control littermates, transgenic mice exhibited high transgene copy numbers, increased Gfrp mRNA and GFRP expression, enhanced GFRP-GTPCH1 interaction, reduced BH4 levels, and low glutathione (GSH) levels and differential mitochondrial bioenergetic profiles. After exposure to total body irradiation, transgenic mice showed decreased BH4/7,8-dihydrobiopterin ratios, increased vascular oxidative stress, and reduced white blood cell counts compared with controls.
  
  
  CONCLUSIONS
  This novel Gfrp knock-in transgenic mouse model allows elucidation of the role of GFRP in the regulation of BH4 biosynthesis. This model is a valuable tool to study the involvement of BH4 in whole body and tissue-specific radiation responses and other conditions associated with oxidative stress.
authors.affiliation: 1 Division of Radiation Health, University of Arkansas for Medical Sciences , Little Rock, Arkansas.
authors.forename: Rupak
authors.initials: R
authors.lastname: Pathak
authors.forename: Snehalata A
authors.initials: SA
authors.lastname: Pawar
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.forename: Prem K
authors.initials: PK
authors.lastname: Gupta
authors.forename: Maaike
authors.initials: M
authors.lastname: Berbée
authors.forename: Sarita
authors.initials: S
authors.lastname: Garg
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Sridharan
authors.forename: Wenze
authors.initials: W
authors.lastname: Wang
authors.forename: Prabath G
authors.initials: PG
authors.lastname: Biju
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Krager
authors.forename: Marjan
authors.initials: M
authors.lastname: Boerma
authors.forename: Sanchita P
authors.initials: SP
authors.lastname: Ghosh
authors.forename: Amrita K
authors.initials: AK
authors.lastname: Cheema
authors.forename: Howard P
authors.initials: HP
authors.lastname: Hendrickson
authors.forename: Nukhet
authors.initials: N
authors.lastname: Aykin-Burns
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress / Q000528:radiation effects*; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing
chemical_list: D001708:Biopterins; D002352:Carrier Proteins; D005978:Glutathione; D030421:Peroxynitrous Acid; D012333:RNA, Messenger; C000592576:GCHFR protein, mouse; C017226:7,8-dihydrobiopterin; C003402:sapropterin