This application is to continue our studies examining the role of von Willebrand factor (VWF) in the pathophysiologyofsicklecelldisease(SCD).DuringthecurrentfundingperiodwehaveshownthatinSCDa) theplasmaconcentrationofVWFisveryhighandthemoleculeishyperadhesive;b)transplantationofmouse SCDbonemarrowintoADAMTS13?/?miceresultsinspontaneousvaso?occlusivecrisis;c)SCDpatientplasma is able to activate endothelial cells to release VWF; d) plasma ADAMTS13 is defective in cleaving multimeric VWFandVWFstrings,butnotasmallpeptidesubstratesuchasthatcurrentlyusedintheclinicalADAMTS13 activity assay; e) VWF from SCD plasma shows less ADAMTS13?mediated proteolysis and more methionine oxidation than control VWF; f) high?dose intravenous infusion of N?acetylcysteine (NAC) decreases VWF multimersize,reducesdensecellformationanderythrocytefragmentation,andincreasestheconcentrationof plasma small molecule thiols. We also have strong evidence that the self?association of VWF is a very important factor in determining its functions, that VWF self?association is enhanced in SCD, and that the processisdecreasedbyplasmahigh?densitylipoprotein(HDL)andacceleratedbythrombospondin?1(TSP?1). We plan to continue our studies of the role of the VWF?ADAMTS13 axis with the following specific aims.
SpecificAim1 :Toidentifythemolecularlesion(s)responsiblefordefectiveADAMTS13cleavageofmultimericVWFin sicklecelldisease.WehavefoundthatADAMTS13proteolysisofmultimericVWFisdefectiveinSCDandwill investigateseveralpossibilitiesforthisdefect.
SpecificAim2 :ToevaluatetheeffectsofTSP?1orApoA?Ideficiency, orApoA?Ioverexpression,onthecourseofdiseaseinsicklemice.Here,wewilltestwhethergeneticconditionsthat eitherdiminishorworsenVWFadhesiveactivityalterthecourseofSCDinmice.
SpecificAim3 :Toevaluatethe effect on the course of SCD in mice of treatment with ADAMTS13, ApoA?I, or VWF, or with both ADAMTS13 and ApoA?I.ThesestudieswillcomplementthoseofSpecificAim2toexplorewhethertreatmentsthatalterVWF adhesiveactivitywillaffecttheacuteorchronicmanifestationsofSCD. WeexpectthesestudiestoprovidefurtherbiologicalinsightsintotherolesinSCDpathophysiologyplayedby theVWF?ADAMTS13axisandoxidativestress.WealsoanticipatethatwewilldiscovernewtargetsforSCD therapy.

Public Health Relevance

Oneofthecharacteristicsofsicklecelldiseaseistheattachmentofbloodcellstobloodvessel walls.Intheapplication,weproposetocontinueworktounderstandtheroleofavesselwall protein,vonWillebrandfactor,inmediatingsomeoftheimportantclinicalmanifestationsofthe disease.Weexpectthisworktoyieldnewtreatmentsforchronicandacuteaspectsofsicklecell disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hemostasis and Thrombosis Study Section (HT)
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Kindzelski, Andrei L
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Puget Sound Blood Center
United States
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Chen, Junmei; Chung, Dominic W (2018) Inflammation, von Willebrand factor, and ADAMTS13. Blood 132:141-147
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