In Vitro Human Tissue-Engineered Blood Vessel Disease Model of Progeria
早衰症体外人体组织工程血管疾病模型
基本信息
- 批准号:9759965
- 负责人:
- 金额:$ 46.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:20 year oldAddressAgingAlternative SplicingAnimal ModelAnimalsAntisense OligonucleotidesApoptosisArterial Fatty StreakArteriesAtherosclerosisAutophagocytosisBacterial Artificial ChromosomesBiological MarkersBlood VesselsCCI-779Cardiovascular DiseasesCardiovascular systemCause of DeathCell AgingCell CountCell Differentiation processCell NucleusCellsCellularityCessation of lifeClinical ResearchCombined Modality TherapyCoronary arteryCultured CellsDevelopmentDiseaseDisease ProgressionDisease modelDrug CombinationsDrug effect disorderEffectivenessEndotheliumEnsureEnvironmentEpigenetic ProcessExhibitsFarnesyl Transferase InhibitorFibroblastsFibrosisGene ExpressionGene MutationGenesHourHumanHuman EngineeringImpairmentIn VitroIndividualInflammationInflammation MediatorsInflammatoryKnock-inLamin Type ALaminsLesionLipidsLonafarnibMeasurementMedialMediatingMethylene blueMitochondriaMitosisModelingMusMyocardial InfarctionNuclearNuclear ProteinOxidative StressParentsPatientsPerfusionPharmaceutical PreparationsPharmacotherapyPhenotypePhysiologicalPoint MutationPravastatinPreparationProcessProductionProgeriaProteinsRNA SplicingRare DiseasesRunningRuptureShapesSignal PathwaySignal TransductionSiteSmooth Muscle MyocytesStrokeStructureSyndromeSystemTestingTherapeuticThickTissue EngineeringTreatment EffectivenessVascular DiseasesZoledronic Acidagedbiomarker identificationcalcificationcarbeneclinical candidatedrug candidatehistone methylationhuman tissueimprovedin vivoin vivo Modelinduced pluripotent stem cellmicrophysiology systemmouse modelnormal agingnovelnovel therapeuticsosteogenicprotein degradationresponse
项目摘要
Abstract
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare autosomal dominant disease of accelerated aging
which leads to death between 7 and 20 years of age. The disease arises from point mutations that produce an
alternately spliced form of the nuclear protein lamin A, known as progerin, that accumulates in the cell nucleus.
Mouse models of HGPS exhibit many phenotypical similarities with the HGPS lamin gene mutation, but
atherosclerosis does not develop, suggesting a limit to the suitability of animal models. Since cardiovascular
disease represents the primary cause of death among those with HGPS, we propose to use a novel tissue
engineered blood vessel microphysiological system to develop biomarkers for the disease and assess the
effectiveness of treatment against relevant physiological measurements. We have developed arteriolar-scale
endothelialized tissue-engineered blood vessels (TEBVs) using smooth muscle cells (SMCs) derived from
induced pluripotent stem cells (iPSCs) using healthy and HGPS cells. The TEBVs can be produced and
perfused at physiological flow conditions within a few hours of preparation and exhibit endothelial-mediated
vasoactivity and respond to inflammatory mediators. We can perform standard functional tests and examine
the effects of inflammatory signals, thus tracking the progression of the disease in the same vessel. The
HGPS-TEBVs provide a more realistic in vitro environment than cells cultured on plastic and can help advance
the process of discovering novel therapeutics and identification of biomarkers. In this project, we will test the
hypotheses that tissue-engineered blood vessels made with cells derived from individuals with HGPS
recapitulate in vitro the structure and activity found in vivo and can aid in assessing the effectiveness and
mode of action suitable drug candidates for clinical studies. In Aim 1, we will test the hypothesis that TEBVs
with cells derived from HGPS patients have the same phenotype as a mouse model of HGPS. We will assess
(1) the relative contribution of reduced cell number and oxidative stress on the altered function of HGPS-
TEBVs, (2) the effect of flow on EC NRF2 activity and oxidative genes it regulates, and (3) compare TEBV
structure and function with the mouse model for HGPS. Control conditions will consist of TEBVs prepared with
cells derived from a parent of one of the HGPS patients. In Aim 2, we will modify our system to run multiple
TEBVs simultaneously and test the hypothesis that combination therapies have been ineffective because they
have not restored SMC number, differentiation, and vasoactivity. In Aim 3, we will assess the suitability of
novel treatments for progeria to alter the HGPS phenotype in the TEBVs. We will examine the effect of agents
which improve mitochondrial function and or protein degradation, alone or in combination with lonafarnib and
anti-sense oligonucleotides that inhibit progerin production. Corresponding studies in mice will be performed to
assess whether the HGPS-TEBV model reproduces changes to vessels found in mouse model of HGPS.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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George A Truskey其他文献
George A Truskey的其他文献
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{{ truncateString('George A Truskey', 18)}}的其他基金
Vascular, Cardiac, and Lung Alveolar Human Microphysiological Systems for SARS-CoV-2 Drug Screening
用于 SARS-CoV-2 药物筛选的血管、心脏和肺泡人体微生理系统
- 批准号:
10166020 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
Developing An In Vitro Human Myobundle Model Of Rheumatoid Arthritis
开发类风湿关节炎的体外人体肌束模型
- 批准号:
9534005 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
Systemic Inflammation in Microphysiological Models of Muscle and Vascular Disease
肌肉和血管疾病微生理模型中的全身炎症
- 批准号:
9401783 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
Systemic Inflammation in Microphysiological Models of Muscle and Vascular Disease
肌肉和血管疾病微生理模型中的全身炎症
- 批准号:
10009489 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
In Vitro Human Tissue-Engineered Blood Vessel Disease Model of Progeria
早衰症体外人体组织工程血管疾病模型
- 批准号:
10445145 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
Systemic Inflammation in Microphysiological Models of Muscle and Vascular Disease
肌肉和血管疾病微生理模型中的全身炎症
- 批准号:
10013428 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
Systemic Inflammation in Microphysiological Models of Muscle and Vascular Disease
肌肉和血管疾病微生理模型中的全身炎症
- 批准号:
10471015 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
In Vitro Human Tissue-Engineered Blood Vessel Disease Model of Progeria
早衰症体外人体组织工程血管疾病模型
- 批准号:
9929937 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
In Vitro Human Tissue-Engineered Blood Vessel Disease Model of Progeria
早衰症体外人体组织工程血管疾病模型
- 批准号:
9980460 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
In Vitro Human Tissue-Engineered Blood Vessel Disease Model of Progeria
早衰症体外人体组织工程血管疾病模型
- 批准号:
10622613 - 财政年份:2017
- 资助金额:
$ 46.21万 - 项目类别:
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