Therapeutic Potential of ALK1 Activating Drugs in HHT Models
Therapeutic Potential of ALK1 Activating Drugs in HHT Models
批准号:
10066360
负责人:
PHILIPPE MARAMBAUD
金额:
$41.25万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-12-15 至 2022-11-30
关键词:
AffectAnimal ModelArteriovenous malformationBloodBlood Coagulation DisordersBlood VesselsBrainCase StudyCell CommunicationCell modelCellsClinicalCollectionDataDefectDevelopmentDiseaseDominant Genetic ConditionsENG geneEndothelial CellsEndotheliumFDA approvedFK506Gene ExpressionGene Expression ProfileGenesGeneticGenetic DiseasesGoalsHereditary hemorrhagic telangiectasiaImmunophilinsIn VitroInterventionIntestinesKnock-in MouseKnockout MiceLaboratoriesLeadLifeLigandsLungMediator of activation proteinMindModelingMolecularMusMutationOrganPathologyPathway interactionsPatientsPharmaceutical PreparationsPropertyReporterReportingResolutionRetinaSignal TransductionSirolimusSymptomsSystemTacrolimusTherapeuticTissuesTranscriptional RegulationUnited States National Institutes of Healthanalogangiogenesisbaseclinical investigationcomparative efficacydrug repurposingeffective therapyimprovedin vivoknock-downloss of functionmouse modelnovelpreventprogramsscreeningtranscriptometranscriptome sequencingtranscriptomics
中文摘要
项目摘要/摘要(描述)
英文摘要
PROJECT SUMMARY/ABSTRACT (DESCRIPTION)
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder characterized by the
development of potentially life-threatening vascular anomalies in several organs in the form of arteriovenous
malformations (AVMs). HHT mutations are mostly found in the ALK1 and ENG genes and lead to a loss-of-
function in the BMP9/10-ALK1-ENG signaling cascade. Evidence suggests that HHT arise from aberrant
reactivation of angiogenesis and endothelial cell (EC)-driven hypervascularization. The overall goal of this
program is to implement a screening and characterization strategy aimed at identifying FDA-approved drugs
with disease-modifying properties and therapeutic potential in novel cellular and mouse models of HHT. We
have screened the NIH clinical collections of FDA-approved drugs to identify molecules capable of activating
ALK1 signaling in reporter cells. The immunophilin ligand tacrolimus (FK506) was identified as the most potent
ALK1 activator. In preliminary studies, we confirmed that tacrolimus, as well as its analog sirolimus, are potent
ALK1 signaling activators in ECs. Of significance, the two analog drugs prevented retinal vascular pathology in
the transmammary model of BMP9/10-immunoblocking, an HHT mouse model recently developed in our
laboratory. In addition, we determined that tacrolimus efficiently triggered ALK1 activation in primary ECs
derived from an HHT patient carrying the well-described disease-causing ALK1-T372fsX mutation. Based on
these results, we propose in Aims 1 and 2 of this application to assess and compare the therapeutic potential
of tacrolimus and sirolimus in the transmammary model of BMP9/10-immunoblocking and in a new knockin
mouse line expressing the HHT ALK1-T372fsX mutation. We will also generate a mini-bank of HHT patient-
derived primary ECs, which will be used to delineate the mechanisms by which tacrolimus and sirolimus
control ALK1 signaling (Aim 3). We believe that this comprehensive approach in relevant and powerful models
of HHT not only will increase our understanding of the molecular underpinnings of the disease, but also will
motivate new clinical investigations for HHT.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Angiopoietin-2 Signaling Targeted Therapeutics for Arteriovenous Malformations
-
批准号:10420883
-
项目类别:
-
资助金额:$70.24万
-
财政年份:2022
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
Angiopoietin-2 Signaling Targeted Therapeutics for Arteriovenous Malformations
-
批准号:10586049
-
项目类别:
-
资助金额:$68.4万
-
财政年份:2022
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
mTOR and VEGFR2 pathways in HHT pathogenesis
-
批准号:10652406
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2020
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
Promotion of Alzheimers Disease by Alcohol - Role of eCIRP
-
批准号:10264903
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2020
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
Promotion of Alzheimers Disease by Alcohol - Role of eCIRP
-
批准号:10689797
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2020
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
mTOR and VEGFR2 pathways in HHT pathogenesis
-
批准号:10229604
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2020
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
mTOR and VEGFR2 pathways in HHT pathogenesis
-
批准号:10434787
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2020
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
Promotion of Alzheimers Disease by Alcohol - Role of eCIRP
-
批准号:10473796
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2020
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
Mechanisms of regulation of amyloid-beta metabolism by CALHM1
-
批准号:8346353
-
项目类别:
-
资助金额:$34.54万
-
财政年份:2013
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
Mechanisms of regulation of amyloid-beta metabolism by CALHM1
-
批准号:8731789
-
项目类别:
-
资助金额:$34.54万
-
财政年份:2013
-
负责人:PHILIPPE MARAMBAUD
-
依托单位:
海外基金