{"id":{"repo_id":"penn","oai_identifier":"oai:repository.upenn.edu:20.500.14332/9439"},"canonical_url":"https://search.dev.ndltd.org/etd/penn/oai:repository.upenn.edu:20.500.14332/9439","repository":{"repo_id":"penn","name":"University of Pennsylvania","base_url":"https://repository.upenn.edu/server/oai/request"},"display":{"title":"The Role of MRGPRX2/Mrgprb2 in Regulating Mast Cell Function","abstract":"Mast\"cells\"(MCs)\"are\"derived\"from\"bone\"marrow\"pluripotent\"hematopoietic\" stem\" cells\" and\" are\" located\" in\" close\" proximity\" to\" the\" external\" environment.\" MCs\" expresses\"several\"receptors\"on\"their\"surface\"such\"as\"the\"high\"affinity\"IgE\"receptor\" (Fc!RI)\"and\"G\"ProteinECoupled\"Receptors\"(GPCRs).\"MRGPRX2\"is\"a\"GPCR,\"which\" consists\"of\"seven\"transmembrane\"domains\"and\"is\"expressed\"exclusively\"in\"MCs\" but\" no\" other\" immune\" cells.\" This\" receptor\" is\" activated\" by\" multiple\" amphipathic\" ligands\" including\" neuropeptides,\" US\" Food\" and\" Drug\" Administration\" (FDA)E approved\"peptidergic\"drugs\"and\"host\"defense\"peptides\"such\"as\"LL_37.\"HDPs\"also\" known\" as\" antimicrobial\" peptides\" (AMPs)\" have\" been\" investigated\" in\" depth\" as\" an\" alternative\"to\"overcome\"antibiotic\"resistance\"crisis.\"However,\"their\"susceptibility\"to\" degradation,\"cytotoxicity\"and\"high\"production\"expenses\"have\"limited\"their\"use.\"To\" overcome\" these\" limitations,\" nonEpeptide\" small\" molecule\" HDP\" mimetics\" (smHDPMs)\" that\" structurally\" resemble\" the\" AMPs\" properties\" but\" have\" better\" stability\"and\"less\"cytotoxicity\"have\"been\"developed.\"We\"utilized\"five\"smHDPMs\"and\" found\" that\" these\" compounds\" demonstrated\" its\" ability\" to\" activate\" MCs\" via\" MRGPRX2.\"This\"raises\"an\"interesting\"possibility\"that\"its\"function\"as\"antimicrobial\" agent\"could\"be\"as\"a\"result\"of\"harnessing\"MCs\"host\"defense\"functions\"beside\"their\" antimicrobial\"activities.\"\" MCs\" can\" also\" participate\" in\" chronic\" inflammatory\" diseases\" when\" innate\" immunity\" is\" dysregulated.\" Rosacea\" is\" a\" chronic\" skin\" disease\" that\" is\" common\" among\"middle\"aged\"Caucasians.\"Human\"rosacea\"skin\"samples\"exhibited\"higher\" 3 number\"of\"MCs\"compared\"to\"normal\"subjects.\"AMP\"LL37\"and\"neuropeptide\"(NP)\" substance\"P\"(SP)\"are\"upregulated\"in\"rosacea.\"LL37\"and\"SP\"activate\"MCs\"through\" MRGPRX2\"in#vitro.#Utilizing\"Mrgprb2\"knockout\"mice\"(Mrgprb2E/E)\"we\"demonstrated\" a\" reduction\" in\" erythema\" presentation,\" inflammatory\" cell\" recruitment,\" MMP+9\" and\" CXCL+2\"mRNA\"expression\"compared\"to\"WT\"mice\"following\"intradermal\"injection\" of\" LLE37\" and\" SP\" to\" rosacea\" model.\" Calcium\" signaling\" is\" essential\" for\" MC\" degranulation\" and\" function.\" In\" this\" dissertation\" we\" present\" an\" evidence\" that\" STIM1/Orai1\" plays\" an\" important\" role\" in\" MRGPRX2\" mediated\" calcium\" influx\" and\" mediators\"release\"when\"stimulated\"with\"LLE37\"and\"SP.\"\" Moreover,\"this\"dissertation\"showed\"naturally\"occurring\"missense\"mutations\" of\" MRGPRX2\" both\" within\" and\" outside\" the\" receptor’s\" predicted\" ligand\" binding\" pocket\" (G165E,\" D184H,\" W243R\" and\" H259Y)\" renders\" it\" unresponsive\" neuropeptides,\" HDPs\" and\" peptidergic\" drugs\" for\" MC\" degranulation.\" Thus,\" individuals\" harboring\" these\" mutations\" may\" develop\" resistance\" to\" drugEinduced\" allergic\"reactions\"and\"rosacea\"but\"may\"display\"increased\"susceptibility\"to\"microbial\" infection.\"\"","abstract_html":"Mast"cells"(MCs)"are"derived"from"bone"marrow"pluripotent"hematopoietic" stem" cells" and" are" located" in" close" proximity" to" the" external" environment." MCs" expresses"several"receptors"on"their"surface"such"as"the"high"affinity"IgE"receptor" (Fc!RI)"and"G"ProteinECoupled"Receptors"(GPCRs)."MRGPRX2"is"a"GPCR,"which" consists"of"seven"transmembrane"domains"and"is"expressed"exclusively"in"MCs" but" no" other" immune" cells." This" receptor" is" activated" by" multiple" amphipathic" ligands" including" neuropeptides," US" Food" and" Drug" Administration" (FDA)E approved"peptidergic"drugs"and"host"defense"peptides"such"as"LL_37."HDPs"also" known" as" antimicrobial" peptides" (AMPs)" have" been" investigated" in" depth" as" an" alternative"to"overcome"antibiotic"resistance"crisis."However,"their"susceptibility"to" degradation,"cytotoxicity"and"high"production"expenses"have"limited"their"use."To" overcome" these" limitations," nonEpeptide" small" molecule" HDP" mimetics" (smHDPMs)" that" structurally" resemble" the" AMPs" properties" but" have" better" stability"and"less"cytotoxicity"have"been"developed."We"utilized"five"smHDPMs"and" found" that" these" compounds" demonstrated" its" ability" to" activate" MCs" via" MRGPRX2."This"raises"an"interesting"possibility"that"its"function"as"antimicrobial" agent"could"be"as"a"result"of"harnessing"MCs"host"defense"functions"beside"their" antimicrobial"activities."" MCs" can" also" participate" in" chronic" inflammatory" diseases" when" innate" immunity" is" dysregulated." Rosacea" is" a" chronic" skin" disease" that" is" common" among"middle"aged"Caucasians."Human"rosacea"skin"samples"exhibited"higher" 3 number"of"MCs"compared"to"normal"subjects."AMP"LL37"and"neuropeptide"(NP)" substance"P"(SP)"are"upregulated"in"rosacea."LL37"and"SP"activate"MCs"through" MRGPRX2"in#vitro.#Utilizing"Mrgprb2"knockout"mice"(Mrgprb2E/E)"we"demonstrated" a" reduction" in" erythema" presentation," inflammatory" cell" recruitment," MMP+9" and" CXCL+2"mRNA"expression"compared"to"WT"mice"following"intradermal"injection" of" LLE37" and" SP" to" rosacea" model." Calcium" signaling" is" essential" for" MC" degranulation" and" function." In" this" dissertation" we" present" an" evidence" that" STIM1/Orai1" plays" an" important" role" in" MRGPRX2" mediated" calcium" influx" and" mediators"release"when"stimulated"with"LLE37"and"SP."" Moreover,"this"dissertation"showed"naturally"occurring"missense"mutations" of" MRGPRX2" both" within" and" outside" the" receptor’s" predicted" ligand" binding" pocket" (G165E," D184H," W243R" and" H259Y)" renders" it" unresponsive" neuropeptides," HDPs" and" peptidergic" drugs" for" MC" degranulation." Thus," individuals" harboring" these" mutations" may" develop" resistance" to" drugEinduced" allergic"reactions"and"rosacea"but"may"display"increased"susceptibility"to"microbial" infection.""","abstract_has_math":false,"creators":["Alkanfari, Ibrahim S"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Hydar Ali"],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-06-21","date_published":"2019-06-21","updated_at":"2026-07-24T03:46:55Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://repository.upenn.edu/handle/20.500.14332/9439","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Hydar Ali"]},{"key":"dc:creator","label":"Author","values":["Alkanfari, Ibrahim S"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2023-05-17T22:10:01.000"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2023-05-22T13:19:35Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2019-06-21T00:00:00Z"]},{"key":"dc:date.issued","label":"Date","values":["2019-06-21"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation/Thesis"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://repository.upenn.edu/handle/20.500.14332/9439"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Mast\"cells\"(MCs)\"are\"derived\"from\"bone\"marrow\"pluripotent\"hematopoietic\" stem\" cells\" and\" are\" located\" in\" close\" proximity\" to\" the\" external\" environment.\" MCs\" expresses\"several\"receptors\"on\"their\"surface\"such\"as\"the\"high\"affinity\"IgE\"receptor\" (Fc!RI)\"and\"G\"ProteinECoupled\"Receptors\"(GPCRs).\"MRGPRX2\"is\"a\"GPCR,\"which\" consists\"of\"seven\"transmembrane\"domains\"and\"is\"expressed\"exclusively\"in\"MCs\" but\" no\" other\" immune\" cells.\" This\" receptor\" is\" activated\" by\" multiple\" amphipathic\" ligands\" including\" neuropeptides,\" US\" Food\" and\" Drug\" Administration\" (FDA)E approved\"peptidergic\"drugs\"and\"host\"defense\"peptides\"such\"as\"LL_37.\"HDPs\"also\" known\" as\" antimicrobial\" peptides\" (AMPs)\" have\" been\" investigated\" in\" depth\" as\" an\" alternative\"to\"overcome\"antibiotic\"resistance\"crisis.\"However,\"their\"susceptibility\"to\" degradation,\"cytotoxicity\"and\"high\"production\"expenses\"have\"limited\"their\"use.\"To\" overcome\" these\" limitations,\" nonEpeptide\" small\" molecule\" HDP\" mimetics\" (smHDPMs)\" that\" structurally\" resemble\" the\" AMPs\" properties\" but\" have\" better\" stability\"and\"less\"cytotoxicity\"have\"been\"developed.\"We\"utilized\"five\"smHDPMs\"and\" found\" that\" these\" compounds\" demonstrated\" its\" ability\" to\" activate\" MCs\" via\" MRGPRX2.\"This\"raises\"an\"interesting\"possibility\"that\"its\"function\"as\"antimicrobial\" agent\"could\"be\"as\"a\"result\"of\"harnessing\"MCs\"host\"defense\"functions\"beside\"their\" antimicrobial\"activities.\"\" MCs\" can\" also\" participate\" in\" chronic\" inflammatory\" diseases\" when\" innate\" immunity\" is\" dysregulated.\" Rosacea\" is\" a\" chronic\" skin\" disease\" that\" is\" common\" among\"middle\"aged\"Caucasians.\"Human\"rosacea\"skin\"samples\"exhibited\"higher\" 3 number\"of\"MCs\"compared\"to\"normal\"subjects.\"AMP\"LL37\"and\"neuropeptide\"(NP)\" substance\"P\"(SP)\"are\"upregulated\"in\"rosacea.\"LL37\"and\"SP\"activate\"MCs\"through\" MRGPRX2\"in#vitro.#Utilizing\"Mrgprb2\"knockout\"mice\"(Mrgprb2E/E)\"we\"demonstrated\" a\" reduction\" in\" erythema\" presentation,\" inflammatory\" cell\" recruitment,\" MMP+9\" and\" CXCL+2\"mRNA\"expression\"compared\"to\"WT\"mice\"following\"intradermal\"injection\" of\" LLE37\" and\" SP\" to\" rosacea\" model.\" Calcium\" signaling\" is\" essential\" for\" MC\" degranulation\" and\" function.\" In\" this\" dissertation\" we\" present\" an\" evidence\" that\" STIM1/Orai1\" plays\" an\" important\" role\" in\" MRGPRX2\" mediated\" calcium\" influx\" and\" mediators\"release\"when\"stimulated\"with\"LLE37\"and\"SP.\"\" Moreover,\"this\"dissertation\"showed\"naturally\"occurring\"missense\"mutations\" of\" MRGPRX2\" both\" within\" and\" outside\" the\" receptor’s\" predicted\" ligand\" binding\" pocket\" (G165E,\" D184H,\" W243R\" and\" H259Y)\" renders\" it\" unresponsive\" neuropeptides,\" HDPs\" and\" peptidergic\" drugs\" for\" MC\" degranulation.\" Thus,\" individuals\" harboring\" these\" mutations\" may\" develop\" resistance\" to\" drugEinduced\" allergic\"reactions\"and\"rosacea\"but\"may\"display\"increased\"susceptibility\"to\"microbial\" infection.\"\""]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Science in Dentistry (DScD)"]},{"key":"dc:title","label":"Title","values":["The Role of MRGPRX2/Mrgprb2 in Regulating Mast Cell Function"]}]}],"canonical_facts":{"dc:contributor.advisor":["Hydar Ali"],"dc:creator":["Alkanfari, Ibrahim S"],"dc:date":["2023-05-17T22:10:01.000"],"dc:date.accessioned":["2023-05-22T13:19:35Z"],"dc:date.available":["2019-06-21T00:00:00Z"],"dc:date.issued":["2019-06-21"],"dc:description.abstract":["Mast\"cells\"(MCs)\"are\"derived\"from\"bone\"marrow\"pluripotent\"hematopoietic\" stem\" cells\" and\" are\" located\" in\" close\" proximity\" to\" the\" external\" environment.\" MCs\" expresses\"several\"receptors\"on\"their\"surface\"such\"as\"the\"high\"affinity\"IgE\"receptor\" (Fc!RI)\"and\"G\"ProteinECoupled\"Receptors\"(GPCRs).\"MRGPRX2\"is\"a\"GPCR,\"which\" consists\"of\"seven\"transmembrane\"domains\"and\"is\"expressed\"exclusively\"in\"MCs\" but\" no\" other\" immune\" cells.\" This\" receptor\" is\" activated\" by\" multiple\" amphipathic\" ligands\" including\" neuropeptides,\" US\" Food\" and\" Drug\" Administration\" (FDA)E approved\"peptidergic\"drugs\"and\"host\"defense\"peptides\"such\"as\"LL_37.\"HDPs\"also\" known\" as\" antimicrobial\" peptides\" (AMPs)\" have\" been\" investigated\" in\" depth\" as\" an\" alternative\"to\"overcome\"antibiotic\"resistance\"crisis.\"However,\"their\"susceptibility\"to\" degradation,\"cytotoxicity\"and\"high\"production\"expenses\"have\"limited\"their\"use.\"To\" overcome\" these\" limitations,\" nonEpeptide\" small\" molecule\" HDP\" mimetics\" (smHDPMs)\" that\" structurally\" resemble\" the\" AMPs\" properties\" but\" have\" better\" stability\"and\"less\"cytotoxicity\"have\"been\"developed.\"We\"utilized\"five\"smHDPMs\"and\" found\" that\" these\" compounds\" demonstrated\" its\" ability\" to\" activate\" MCs\" via\" MRGPRX2.\"This\"raises\"an\"interesting\"possibility\"that\"its\"function\"as\"antimicrobial\" agent\"could\"be\"as\"a\"result\"of\"harnessing\"MCs\"host\"defense\"functions\"beside\"their\" antimicrobial\"activities.\"\" MCs\" can\" also\" participate\" in\" chronic\" inflammatory\" diseases\" when\" innate\" immunity\" is\" dysregulated.\" Rosacea\" is\" a\" chronic\" skin\" disease\" that\" is\" common\" among\"middle\"aged\"Caucasians.\"Human\"rosacea\"skin\"samples\"exhibited\"higher\" 3 number\"of\"MCs\"compared\"to\"normal\"subjects.\"AMP\"LL37\"and\"neuropeptide\"(NP)\" substance\"P\"(SP)\"are\"upregulated\"in\"rosacea.\"LL37\"and\"SP\"activate\"MCs\"through\" MRGPRX2\"in#vitro.#Utilizing\"Mrgprb2\"knockout\"mice\"(Mrgprb2E/E)\"we\"demonstrated\" a\" reduction\" in\" erythema\" presentation,\" inflammatory\" cell\" recruitment,\" MMP+9\" and\" CXCL+2\"mRNA\"expression\"compared\"to\"WT\"mice\"following\"intradermal\"injection\" of\" LLE37\" and\" SP\" to\" rosacea\" model.\" Calcium\" signaling\" is\" essential\" for\" MC\" degranulation\" and\" function.\" In\" this\" dissertation\" we\" present\" an\" evidence\" that\" STIM1/Orai1\" plays\" an\" important\" role\" in\" MRGPRX2\" mediated\" calcium\" influx\" and\" mediators\"release\"when\"stimulated\"with\"LLE37\"and\"SP.\"\" Moreover,\"this\"dissertation\"showed\"naturally\"occurring\"missense\"mutations\" of\" MRGPRX2\" both\" within\" and\" outside\" the\" receptor’s\" predicted\" ligand\" binding\" pocket\" (G165E,\" D184H,\" W243R\" and\" H259Y)\" renders\" it\" unresponsive\" neuropeptides,\" HDPs\" and\" peptidergic\" drugs\" for\" MC\" degranulation.\" Thus,\" individuals\" harboring\" these\" mutations\" may\" develop\" resistance\" to\" drugEinduced\" allergic\"reactions\"and\"rosacea\"but\"may\"display\"increased\"susceptibility\"to\"microbial\" infection.\"\""],"dc:description.degree":["Doctor of Science in Dentistry (DScD)"],"dc:identifier.uri":["https://repository.upenn.edu/handle/20.500.14332/9439"],"dc:title":["The Role of MRGPRX2/Mrgprb2 in Regulating Mast Cell Function"],"dc:type":["Dissertation/Thesis"]},"updated_at":"2026-07-24T03:46:55Z"}