Abstract

Thisproposalwilltestthehypothesisthatradiation-inducedlatelungandhearttoxicitiesareaconsequenceof endothelialdysfunctiondefinedasuncouplednitricoxidesynthetaseactivityanddecreasednitricoxide bioavailabilityestablishingastateofchronicinflammationdrivingapersistentpro-fibroticprocessassociated withabnormalwoundrepairandlatenormaltissueinjury.Forradiationasub-lethaldosethatinducesthe hematopoieticsyndrome(5Gy)immediatelyfollowedbythoraxonly?top-up?of6.5Gywillbeusedasthe radiationprotocol.Theproposalwilltestwhethersepiapterin,ametabolicprecursoroftetrahydrobiopterin,or inductionoftheinflammatoryprotein,hemeoxygenase-1,24hourspostIRre-establishesanormalwound repairmechanismremovingthedrivingforceforchronicinflammationandfibrosis.Theproposedexperiments alsotestwhetherexosomesshedfromirradiatedendothelialcellsprovidepotentialbiomarkersforthelate effectsofradiation.
AIM1 Hypothesis:radiationuncouplesnitricoxidesynthetaseactivitybyreducing tetrahydrobiopterinincardiacandlungendothelialcellsinvitroandthisresultsendothelialcelldysfunctionas evaluatedbymarkersofinflammation,senescenceandendothelial-mesenchymaltransition.
AIM2 Hypothesis:oraladministrationofsepiapterinorinductionofhemeoxygenase-1expressionwithhemin24 hoursafteraradiationexposure,enhanceslungandcardiacfunctionasevidencedbydecreasedbreathing frequency,decreasedinflammation,enhancedcontractilereserve,improvedrelaxationanddiastolicfunction, reducedfibrosisandenhancedsurvival.
AIM3 Hypothesis:exosomesandtheircargopurifiedfromtheplasma ofirradiatedmiceinAim2andfromtheplasmaofpatientstreatedbyradiotherapyforlungandbreastcancer stimulateendothelialcelldysfunctionandrepresentapotentialsourceofbiomarkersforlungandcardiacinjury followingradiation.

Public Health Relevance

Thisproposalteststhehypothesisthatheartandlunginjuryasaconsequenceofa nucleareventisduetouncouplednitricoxidesynthaseactivityresultinginendothelial celldysfunctionandsenescence.Theproposalteststherapeuticapproachesto overcomethisuncouplingthatareinclinicaltrialsforthetreatmentofvasculardiseases andthusshouldbereadilytranslatedintotheclinicinthetreatmentofradiation-induced normaltissueinjury.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI133595-04
Application #
9934108
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Vedamony, Merriline M
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Virginia Commonwealth University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298