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:
    10013428
  • 负责人:
  • 金额:
    $ 25.09万
  • 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

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(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:
    $ 25.09万
  • 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:
    $ 25.09万
  • 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:
    $ 25.09万
  • 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:
    $ 25.09万
  • 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:
    $ 25.09万
  • 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:
    $ 25.09万
  • 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:
    $ 25.09万
  • 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:
    $ 25.09万
  • 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:
    $ 25.09万
  • 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:
    $ 25.09万
  • 项目类别:

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