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
基本信息
- 批准号:10471015
- 负责人:
- 金额:$ 7.33万
- 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 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelAnti-Inflammatory AgentsAntibodiesArteriesAtherosclerosisAttenuatedAutoimmune DiseasesBiological MarkersBiological ModelsBiomechanicsBlood VesselsCRISPR/Cas technologyCardiacCardiovascular DiseasesCell ProliferationCellsCholesterolChronicChronic DiseaseClinicalClustered Regularly Interspaced Short Palindromic RepeatsDevelopmentDiseaseDisease ProgressionDisease modelDrug ModelingsEndothelial CellsEndotheliumEnvironmentEventExerciseExposure toFeedbackFoam CellsFunctional disorderGene ExpressionGenesGenetic VariationGoalsHeartHumanImmuneImmune responseIn VitroIndividualInflammationInflammatoryInflammatory ResponseInterleukin 6 ReceptorInterleukin-6LaboratoriesLipid-Laden MacrophageLipidsLipoproteinsLiquid substanceLow-Density LipoproteinsMediatingModelingMuscleMuscle functionMuscular AtrophyMutationMyocardiumMyopathyPathologyPatternPerfusionPharmaceutical PreparationsPharmacotherapyPhasePhenotypePopulationProcessProprotein ConvertasesProteinsRheumatoid ArthritisRiskRoleSeveritiesSeverity of illnessSingle Nucleotide PolymorphismSiteSkeletal MuscleSmooth Muscle MyocytesStructureSubtilisinsSymptomsSystemTechnologyTestingTherapeutic InterventionTherapeutic exerciseTissue EngineeringTissuesVariantVascular Diseasesbasecardiovascular disorder riskclinically relevantcytokinedisease phenotypedrug developmentdrug discoverydrug testingeffectiveness testingendothelial dysfunctiongain of function mutationgenetic varianthuman diseaseimprovedin vitro Modelin vivoinduced pluripotent stem celljoint inflammationloss of functionloss of function mutationmacrophagemicrophysiology systemnovel therapeuticspopulation basedprogression markerrepairedresponseshear stressspatial temporal variationsystemic inflammatory responsetherapeutic target
项目摘要
ABSTRACT
The initiation and progression of atherosclerosis is influenced by systemic inflammation and individuals
suffering from autoimmune diseases, such as rheumatoid arthritis, have increased risk of developing
cardiovascular diseases. Likewise, chronic and systemic inflammation in rheumatoid arthritis induces muscle
wasting and loss of function. Therapies that reduce inflammation effectively treat rheumatoid arthritis and
have the potential to reduce the severity of cardiovascular disease. To overcome limitations of animal
models replicating some key disease phenotypes, but not the underlying mechanisms, we established
functional human microphysiological systems (hMPS) for healthy human skeletal and cardiac muscle and
endothelialized tissue-engineered blood vessels (eTBEVs) using primary and iPS-derived cells and assessed
the response to drugs and pro-inflammatory cytokines. These models replicate the structure and key functions
of the native tissue and maintain their structure and function for at least 4 weeks. These in vitro tissue
systems accurately model the response to drugs. Our goal in this project is to develop clinically relevant
hMPS disease models to examine rheumatoid arthritis (RA) risk for muscle dysfunction and atherosclerosis
and the role of exercise in attenuating disease-associated inflammation. To meet this goal, we will expand our
preliminary results to develop and validate an early atherosclerosis model that uses flow conditions promoting
endothelial dysfunction, macrophage accumulation, foam cell formation, and altered vasoactivity. We will
reproduce the RA phenotype in skeletal and cardiac muscle through addition of macrophages and cytokines
present in RA, and demonstrate that simulated exercise conditions on muscle produce myokines that reduce
inflammation in this RA model. Then, we will develop an integrated perfusion system for eTEBVs, skeletal
and cardiac muscle and show that the RA model can increase macrophage accumulation in eTEBVs and
cardiac bundles, and assess the response to exercise and drugs to treat atherosclerosis and inflammation.
We will use CRISPR gene editing technology to generate mutations to proprotein convertase subtilisin/kexin
type 9 (PCSK9) and genes that affect IL-6 shedding to assess their impact on endothelial dysfunction and
foam cell formation in eTEBVs, and inflammation in skeletal and cardiac muscle bundles. We will profile
cytokines and metabolites in the models with and without RA, and demonstrate that disease progression and
biomarkers are reduced in the presence of common anti-inflammatory therapeutic interventions for
atherosclerosis, and assess the effect of exercise. Likewise, in the RA muscle model, we will examine whether
gene variants produce alterations in cytokine profiles impacting muscle function and response to exercise;
these may point toward new disease-associated biomarkers and therapeutic targets. Results of this project
will provide a general framework for in vitro modeling of atherosclerosis and autoimmune diseases and the
role of gene variants in disease severity and drug development.
摘要
项目成果
期刊论文数量(3)
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
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:
9759965 - 财政年份:2017
- 资助金额:
$ 7.33万 - 项目类别:
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:
$ 7.33万 - 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:
$ 7.33万 - 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:
$ 7.33万 - 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:
$ 7.33万 - 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:
$ 7.33万 - 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:
$ 7.33万 - 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:
$ 7.33万 - 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:
$ 7.33万 - 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:
$ 7.33万 - 项目类别:
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