Vascular remodeling in patients with rare genetic disorders
罕见遗传性疾病患者的血管重塑
基本信息
- 批准号:10929131
- 负责人:
- 金额:$ 182.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:5&apos-NucleotidaseAccelerationAdhesionsAdultAffectAneurysmArterial IntimasArteriesAtherosclerosisAtherosclerosis Risk in CommunitiesBenignBiological AssayBiological ModelsBlood VesselsBlood flowCADASILCOVID-19 patientCalciumCandidate Disease GeneCardiacCell LineCellsChildhoodChoristomaChronicChronic DiseaseChronic Kidney FailureChronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatureClinicalClinical ResearchCoculture TechniquesCollaborationsCollagenCommunicationComplexComplicationConnective TissueCutaneousDNA Sequence AlterationDasatinibDataData AnalysesDefectDegos diseaseDermalDiagnosticDilatation - actionDiseaseDisease OutcomeDisease ProgressionDisease modelDrug ScreeningEchocardiographyElectrocardiogramEndothelial CellsEndotheliumEnrollmentEnzymesEtiologyEvaluationExonsExtracellular MatrixExtravasationFaceFatal OutcomeFibroblastsFibrosisFunctional disorderGene MutationGeneral PopulationGenesGeneticGrantGranulation TissueHaplotypesHealthHepatomegalyImmuneImmune systemImmunologic Deficiency SyndromesIn VitroInfectionInflammationInheritedIntegrinsIntellectual functioning disabilityIntercellular adhesion molecule 1Job&aposs SyndromeJointsLYN geneLifeLiver FibrosisLower ExtremityLungMagnetic Resonance ImagingManuscriptsMapsMediatingMemory LossMesenchymalMetabolic PathwayMetabolismMicrovascular DysfunctionMicrovascular PermeabilityMigraineModelingMolecularMultiple AbnormalitiesMutationMyocardial InfarctionNOTCH3 geneNational Heart, Lung, and Blood InstituteNatural HistoryNatureNeonatal Onset Multisystem Inflammatory DiseaseNeutrophil InfiltrationNon-Insulin-Dependent Diabetes MellitusNucleotidasesOrganOutcomeOxygenPathway interactionsPatientsPerinatalPerivascular FibrosisPharmaceutical PreparationsPhasePhenotypePhosphotransferasesPopulationProlineProteinsProteomicsPublishingPulmonary HypertensionPurinesRare DiseasesReportingResearchResearch TechnicsResourcesRisk FactorsRoleSTAT3 geneSignal PathwaySignal TransductionSpleenStrokeSubarachnoid HemorrhageSystemSystemic hypertensionTBK1 geneTNF geneTechnologyTestingTherapeuticTimeTissuesTreatment ProtocolsVascular DiseasesVascular Endothelial CellVascular blood supplyVascular calcificationVascular remodelingVascularizationVasculitisXaa-Pro dipeptidaseangiogenesisarterial tortuosityautoinflammatory diseasesautosomebiobankbiomarker identificationbody systemcalcificationclinical trial analysisdatabase of Genotypes and Phenotypesdisease-causing mutationeffectiveness testingextracellulargain of function mutationgenetic testinghealinghealth recordhypoperfusionhypoxia inducible factor 1imaging studyimprovedin vivoinduced pluripotent stem cellinflammatory modulationinhibitorinsightkinase inhibitorlarge datasetsmigrationmouse modelneutrophiloptical imagingpost-COVID-19programspsychiatric symptomrare genetic disorderrecessive genetic traitrecurrent infectionresearch clinical testingscreeningside effectsingle cell sequencingskin lesionskin ulcerslugsrc-Family Kinasessystemic inflammatory responsetherapeutic targettooltranscriptome sequencingtreatment strategyvascular abnormalitywhole genomewound healing
项目摘要
Monogenetic disorders grant the unique ability to understand more complex diseases due to a single defined genetic defect. Advanced sequencing technology accelerates gene candidate discovery but progress can be slowed by the inability to distinguish between functional disease related and non-disease related mutations. We use patient-specific in vitro disease modeling systems combined with genetic tools to identify disease related mutation, to study gene related disease mechanism and to perform drug screening. Further, comprehensive clinical evaluation of patients with these conditions further help elucidate the disease mechanism and the organ systems affected.
Vascular calcification is a secondary complication to diseases such as atherosclerosis, diabetes mellitus type II and chronic kidney disease but its underlying mechanism is poorly understood. ACDC is a rare disease, in which de novo vascular calcifications form in lower extremity arteries and peri-articular calcifications in the joints of affected adults and is caused by mutations in the 5'-nucleotidase Ecto (NT5E) gene encoder for CD73, an enzyme in the extracellular purine metabolic pathway. Our small non-randomized treatment protocol in seven patients with ACDC with etidronate that was completed in 2021 tested effectiveness of etidronate in attenuating the progression of lower extremity arterial/peri-articular calcification formation and improving vascular blood flow. Results showed that etidronate treatment did not significantly change these parameters over time but may have slowed the rate disease progression. Patients tolerated the medication well with no significant side effects. A manuscript summarizing this data is currently under review.
Autosomal dominant hyper-IgE syndrome (AD-HIES; Jobs syndrome) is a rare immunodeficiency due to mutations in the STAT3 gene. Patients suffer from multiple life-threatening infections from childhood as well as multiple abnormalities outside the immune system, such as aberrant healing. Vascular abnormalities include arterial tortuosity and abnormal dilatation and aneurysms of medium sized arteries, potentially leading to myocardial infarction and subarachnoid hemorrhage. In a wound healing assay, we found delayed granulation tissue formation and vascularization in AD-HIES patients compared to healthy subjects. RNA-Seq analysis identified deficiencies in angiogenesis, extracellular matrix metabolism, and wound healing signaling pathways mediated by dysregulation of HIF1 signaling. Currently, we continue to look for therapeutic targets for AD-HIES patients within signaling pathways affected by deficient HIF1 signaling.
Prolidase deficiency (PD) is an autosomal recessive genetic disease caused by mutations in the PEPD gene encoding the enzyme prolidase D, leading to defects in turnover of proline-containing proteins, such as collagen. PD is characterized by chronic severe skin ulcers, recurrent infections, unusual facial features, variable intellectual disability levels, and enlargement of the liver and spleen. To determine the wound healing phenotype in PD patients, we established PD patient-specific iPSC-derived endothelial cell (EC) lines and primary dermal fibroblasts lines. We plan to use single culture/co-culture systems in combination with in vitro scratch wound healing/angiogenesis assays to determine the role of vascular endothelial cells and dermal fibroblasts in PD wound healing as well as to test different kinds of treatment.
Autoinflammatory diseases, such as SAVI, DADA2, NOMID, CANDLE and LYN GOF, negatively impact blood vessels, resulting in severe tissue damage as well as fatal outcomes for those affected. These diseases are caused by genetic mutations and underlying mechanisms have not been well characterized. We investigate these through clinical evaluation, genetic testing, high content screening and single cell sequencing as well as patient derived cells to investigate the disease mechanisms with in vitro/in vivo murine models. Endothelial-to-mesenchymal transition (EndMT) is a major mechanism contributing to multiple organ fibrosis. During the reporting period, we identified that spontaneously developed SAVI iEC (induced pluripotent stem cell-derived endothelial cells). EndMT contributes to perivascular fibrosis in SAVI patient lung sections. We further determined that the STING/TBK1/STAT3/Slug pathway mediates EndMT and identified potential treatments including STING, TBK1 and JAK/STAT inhibitors using a SAVI-iEC disease model. We also established an iEC/iSMC coculture in-vitro disease model for CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), which is associated with systemic and pulmonary hypertension. This model will allow us to further explore underlying disease mechanisms and test potential therapeutic tools for CANDLE.
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. The pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. In the last year, we identified three unrelated patients with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation caused by constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on iECs and of 2-integrins on patient neutrophils, implicated in increased neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis. These results were published on Nature Communications in March 2023.
Small vessel diseases are conditions with narrowing of small arteries leading to an imbalance of blood supply upon demand, resulting in progressive chronic hypoperfusion with detrimental outcomes. CADASIL is caused by NOTCH3 mutations with predominant clinical features including migraines, strokes, memory loss, and multiple psychiatric symptoms. Similarly, Kholmeier-Degos (K-D) disease is a poorly understood rare vasculopathy leading to small vessel occlusions in multiple organs. Benign K-D is specifically limited to skin lesions, while systemic K-D progresses to other organs and may quickly become fatal. We developed a robust clinical research program to characterize the etiology/natural history of CADASIL and K-D through comprehensive clinical and molecular evaluations as well as to develop patient-derived disease models to better understand their pathophysiology.
To compare disease progression in patients with rare diseases with similar clinical presentation to that of more common diseases, we have incorporated population data analysis from clinical trials and health records in our vascular diseases program. Large population data has recently become available through resources such as the NHLBI BioLINCC, dbGaP or UK Biobank. We are working to develop increased expertise in obtaining and analyzing these large datasets. As a result, we have analyzed data from the Atherosclerosis Risk in Communities (ARIC) study identifying risk factors for chronic diseases (PMID: 37245480; PMID: 36599719) and are currently working to integrate this analysis of risk factors with insights related to gene-disease interactions from rare disease research.
We also have on-going collaborations to evaluate post-COVID19 patients with a focus on long-term cardiac and vascular sequelae. We assess cardiac and vascular health of these patients with a variety of research techniques including electrocardiograms, echocardiograms, cardiac MRIs, optical imaging studies, NIRS, etc.
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Development of vascular disease models to explore disease causation and pathomechanisms of rare vascular diseases.
- DOI:10.1007/s00281-022-00925-9
- 发表时间:2022-05
- 期刊:
- 影响因子:9
- 作者:Harper RL;Ferrante EA;Boehm M
- 通讯作者:Boehm M
Diffuse atrophic papules and plaques, intermittent abdominal pain, paresthesias, and cardiac abnormalities in a 55-year-old woman.
一名 55 岁女性出现弥漫性萎缩性丘疹和斑块、间歇性腹痛、感觉异常和心脏异常。
- DOI:10.1016/j.jaad.2016.09.015
- 发表时间:2016
- 期刊:
- 影响因子:13.8
- 作者:Oliver,Brittany;Boehm,Manfred;Rosing,DouglasR;Shapiro,LeeS;Dempsey,DanielT;Merkel,PeterA;Lee,Chyi-ChiaRichard;Cowen,EdwardW
- 通讯作者:Cowen,EdwardW
4D Printed Cardiac Construct with Aligned Myofibers and Adjustable Curvature for Myocardial Regeneration.
- DOI:10.1021/acsami.0c17610
- 发表时间:2021-03-24
- 期刊:
- 影响因子:9.5
- 作者:Wang, Yue;Cui, Haitao;Wang, Yancheng;Xu, Chengyao;Esworthy, Timothy J.;Hann, Sung Yun;Boehm, Manfred;Shen, Yin-Lin;Mei, Deqing;Zhang, Lijie Grace
- 通讯作者:Zhang, Lijie Grace
Middle-age high normal serum sodium as a risk factor for accelerated biological aging, chronic diseases, and premature mortality.
- DOI:10.1016/j.ebiom.2022.104404
- 发表时间:2023-01
- 期刊:
- 影响因子:11.1
- 作者:Dmitrieva, Natalia I.;Gagarin, Alessandro;Liu, Delong;Wu, Colin O.;Boehm, Manfred
- 通讯作者:Boehm, Manfred
CADASIL: new advances in basic science and clinical perspectives.
- DOI:10.1097/moh.0000000000000497
- 发表时间:2019-05
- 期刊:
- 影响因子:3.2
- 作者:Ferrante EA;Cudrici CD;Boehm M
- 通讯作者:Boehm M
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Manfred Boehm其他文献
Manfred Boehm的其他文献
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{{ truncateString('Manfred Boehm', 18)}}的其他基金
iPS-technology and patient specific disease models
iPS 技术和患者特定疾病模型
- 批准号:
8746650 - 财政年份:
- 资助金额:
$ 182.63万 - 项目类别:
iPS-technology and patient specific disease models
iPS 技术和患者特定疾病模型
- 批准号:
8939854 - 财政年份:
- 资助金额:
$ 182.63万 - 项目类别:
iPS-technology and patient specific disease models
iPS 技术和患者特定疾病模型
- 批准号:
9157402 - 财政年份:
- 资助金额:
$ 182.63万 - 项目类别:
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