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Principal Investigator: Edda Frauke Spiekerkoetter
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $688,595
Funding agency: National Heart Lung and Blood Institute
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by multiple arteriovenous
malformations (AVMs) which are direct connections between arteries and veins, bypassing the capillary bed.
Pulmonary AVMs (PAVMs) are the most common visceral AVMs in adult (10-45%) and pediatric HHT patients
(60%) and cause significant morbidity and mortality due to an increased risk for cerebral abscesses, stroke,
pulmonary hemorrhage and migraines. Current treatment for PAVMs consists of catheter mediated embolization
with a re-perfusion rate of up to 25%, necessitating frequent imaging (radiation exposure) as well as repeat
interventions. While heterozygous loss-of function mutations in ENDOGLIN, ALK1 and SMAD4 are responsible
for the development of HHT in 85% of patients, we still do not know precisely how PAVMs develop. In
particular, we do not know exactly from which vascular bed (arterial, capillary, venous) PAVMs arise, and which
downstream signaling pathway is most important for PAVM development or growth that could be harnessed as
a therapeutic target. No medical therapy exists that is able to prevent, arrest growth or even reverse
PAVMs. Furthermore, we are lacking precise animal models of PAVMs or in vitro disease models, necessary
for pre-clinical testing of therapeutic approaches. We therefore hypothesized that understanding the cellular
and molecular mechanisms governing PAVM development paired with the identification of clinically relevant,
pathological signaling abnormalities will allow us to develop and test novel therapeutic approaches that prevent
and potentially reverse disease. Our proposal has three significant parts, which are represented by our three
specific aims: First, to develop and characterize a novel mouse model of PAVM formation by deleting HHT
causing genes in different endothelial cell subpopulations and study their role in PAVM development and growth.
Second, to differentiate induced pluripotent stem cells (iPSCs) from HHT patients into arterial and venous
endothelial cells (ECs), to identify novel common or unique pathways altered in HHT as a direct consequence of
mutations in ENG, ALK1 and SMAD4, to predict repurposed drugs (in silico) and test whether they target the
newly identified pathways in iPSC-ECs and tissue culture. Third, to test whether lead candidate drugs, FK506
and Enzastaurin, and novel drugs identified in Aim 2 (ie Brivanib, see preliminary data) positively influence PAVM
formation, growth and potential regression. Our proposal is innovative because it combines a conceptionally
novel approach (understanding PAVM development by focusing on disease-causing alterations in
subpopulations of lung endothelial cells) with cutting edge techniques (multiplex single-molecule fluorescence
in situ hybridization, spatial transcriptomics, multicolor labeling and high resolution 3-D imaging of the lung) and
novel pharmacological interventions (drugs identified by High-Throughput Screening, predicting novel drugs
in silico).The short-term impact will be a better understanding of how AVMs form in the lung and potentially in
other organs (brain, skin). The long-term impact will be the identification of potential novel treatments for AVMs.
Terms: <0-11 years old><21+ years old><3-D Imaging><3D imaging><Ablation><Abnormal Endothelial Cell><Adult><Adult Human><Alimentary Canal><Allelic Loss><Animal Model><Animal Models and Related Studies><Apoplexy><Apoptosis><Apoptosis Pathway><Arteries><Arteriovenous Angioma><Arteriovenous Hemangioma><Arteriovenous malformation><BMPR-II><BMPR2><BMPR2 gene><BRK-3 protein><Bleeding><Blood capillaries><Body Tissues><Bone Morphogenetic Protein Receptor, Type II (Serine/Threonine Kinase) Gene><Brain><Brain Nervous System><Brain Vascular Accident><Bypass><CD105 Antigen><CRISPR correction><CRISPR-based correction><Cas9-based correction><Cas9-mediated correction><Catheters><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cerebral Abscesses><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Child><Child Youth><Childhood><Children (0-21)><Clinical Trials><Color><Conceptions><DPC4><Data><Deleted in Pancreatic Carcinoma><Development><Digestive Tract><Disease><Disorder><Dominant Genetic Conditions><Dominant trait><Drosophila Homolog of Mothers Against Decapentaplegic 4><Drugs><Dysfunction><Embolization Therapy><Embolotherapy><Encephalon><Endoglin><Endothelial Cells><Endothelium><Epistaxis><Event><FISH Technic><FISH Technique><FISH analysis><FISH assay><FK 506><FK506><Fluorescence In Situ Hybridization><Fluorescent in Situ Hybridization><Functional disorder><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Dominant><Genetic defect><Growth><Growth and Development><Growth and Development function><Health><Hemorrhage><Hereditary hemorrhagic telangiectasia><Heterozygote><High Throughput Assay><Human><Image><In Vitro><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Label><Life><Liver><Loss of Heterozygosity><Lung><Lung Respiratory System><MADH4><MADH4 gene><Maps><Mediating><Medical><Medication><Mice><Mice Mammals><Migraine><Migraine Headache><Mission><Modern Man><Molecular><Molecular Target><Morbidity><Morbidity - disease rate><Murine><Mus><Mutation><NIH><Nasal Hemorrhage><Nasal Mucosa><National Institutes of Health><Nose Bleed><Nosebleed><Organ><Organ Culture><Organ Culture Techniques><Osler-Rendu Disease><Osler-Weber-Rendu Disease><PBMC><Pathologic><Pathway interactions><Patients><Penetrance><Peripheral Blood Mononuclear Cell><Pharmaceutical Preparations><Phenotype><Physiologic pulse><Physiopathology><Population><Preclinical Testing><Prevalence><Prevention><Programmed Cell Death><Proliferating><Pulmonary AVMs><Pulmonary imaging><Pulse><RNA Seq><RNA sequencing><RNAseq><Racemose Angioma><Racemose Hemangioma><Radiation exposure><Reperfusion Therapy><Research><Resolution><Risk><Role><SMA- and MAD-Related Protein 4><SMAD4><Short interfering RNA><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Slice><Small Interfering RNA><Stroke><Structure of mucous membrane of nose><Subcellular Process><Tacrolimus><Techniques><Telangiectasia><Telangiectasis><Testing><Therapeutic><Therapeutic Embolization><Three-Dimensional Imaging><Tissue Growth><Tissues><Transforming Growth Factor P Receptor III><Tube><United States National Institutes of Health><Vascular Endothelial Cell><Veins><Venous><Visceral><adulthood><alimentary tract><autosome><biological signal transduction><blood loss><bone morphogenetic protein receptor II><bone morphogenetic protein receptor type II><brain attack><capillary><capillary bed><cell behavior><cell type><cellular behavior><cerebral vascular accident><cerebrovascular accident><clinical relevance><clinically relevant><common symptom><death risk><developmental><digestive canal><disability><disease model><disorder model><drug candidate><drug development><drug repositioning><drug repurposing><drug/agent><embolization><genetic condition><genetic disorder><genome mutation><hepatic body system><hepatic organ system><heterozygosity><high throughput screening><high-throughput drug screening><iPS><iPSC><iPSCs><imaging><improved><in silico><in vitro Organ Culturing><in vitro vertebrate organ culturing><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><innovate><innovation><innovative><interventional strategy><kids><knock-down><knockdown><lead candidate><loss of function mutation><lung AVMs><lung imaging><lung microvascular endothelial cells><lung scanning><lung vascular endothelial cells><model of animal><mortality><mortality risk><mouse model><murine model><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ontogeny><pathophysiology><pathway><pediatric><pharmacologic><postnatal><pre-clinical testing><prevent><preventing><pulmonary><pulmonary arterial hypertension><pulmonary arteriovenous malformation><pulmonary artery hypertension><pulmonary microvascular endothelial cells><pulmonary vascular endothelial cells><reperfusion><repurposing agent><repurposing medication><resolutions><siRNA><single molecule><social role><stroked><strokes><therapeutic evaluation><therapeutic target><therapeutic testing><tissue culture><tool><transcriptome sequencing><transcriptomic sequencing><transcriptomics><type II BMP receptor><vascular bed><youngster>