Rebuilding the Lung

重建肺部

• 批准号: 8044042
• 负责人: Angela Panoskaltsis-Mortari
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044042
• 关键词: 3-Dimensional; Adult; Air; Aorta; Applications Grants; Biological Models; Biomedical Engineering; Bioreactors; Blood; Bronchiolitis; Cell Differentiation process; Cell Therapy; Cell-Matrix Junction; Cells; Characteristics; Chemicals; Chronic; Chronic Obstructive Airway Disease; Clinical Trials; Cultured Cells; Cystic Fibrosis; Data; Development; Endothelial Cells; Endothelium; Environment; Environmental air flow; Epithelial; Epithelial Cells; Epithelium; Evaluation; Extracellular Matrix; Fetal Lung; Generations; Goals; Grant; Growth; Growth Factor; Hamman-Rich syndrome; Head; Implant; Infusion procedures; Interstitial Lung Diseases; Liquid substance; Lung; Lung Transplantation; Lung diseases; Mesenchymal Stem Cells; Mus; Organ; Organ Donor; Patients; Pattern; Pluripotent Bone Marrow Stem Cell; Pluripotent Stem Cells; Population; Positioning Attribute; Process; Protein C Inhibitor; Proteins; Pulmonary Emphysema; Pump; Rattus; Reporting; Right ventricular structure; Rodent; Source; Staging; Stem cells; Stretching; Structure of parenchyma of lung; System; TACSTD2 gene; Technical Expertise; Testing; Time; Tissues; Trachea; Transplantation; Vascular Endothelium; cell growth; experience; fetal; injured; interest; lung basal segment; mortality; novel; progenitor; public health relevance; pulmonary arterial hypertension; repaired; scaffold; success; translational study

DESCRIPTION (provided by applicant): Our ultimate goal is to rebuild the lung using decellularized lung as a natural 3-dimensional (3-D) matrix base for lung progenitor cells. Lung transplantation is usually the only option for patients with irreversible structural lung damage but is hindered by major obstacles such as lack of lung organ donors and chronic rejection. Artificial scaffolds cannot replicate the branching or the composition, arrangement and stretch of the extracellular matrix of the lung. We will focus on rebuilding the lung using ventilated, decellularized whole lungs as a natural 3-D matrix and repopulate it with cells having potential as lung epithelial and endothelial progenitors. We have data that rodent lungs can successfully be decellularized while maintaining extracellular matrix in the correct geospatial branching pattern even after prolonged ventilation. Adult and fetal lung cells can successfully be infused and cultured in decellularized, ventilated lungs. We hypothesize that, given the right growth conditions, putative progenitors will re-epithelialize and re-endothelialize the matrix and produce proteins characteristic of lung cells. We also expect that timing of cell input, growth factors and developmental stage-appropriate ventilatory stretch will be critical to this process. In Aim 1, we will determine if putative lung progenitor cell populations such as induced pluripotent (iPS) cells, BM-derived cells and EpCAM+ lung-derived cells, will grow and differentiate in the setting of a ventilated, decellularized, whole lung matrix in our new "lung bioreactor" system. We will compare culturing these cells, alone and in combination, in decellularized matrices prepared from adult and fetal lungs. In Aim 2, we will determine if both epithelium and endothelium can be recellularized using blood outgrowth endothelial cells (BOECs) and the best cells from Aim 1. We are in a unique position to perform these studies. We have a unique model system and highly experienced collaborators who provide novel cells, critical expertise and advice for this grant application. PUBLIC HEALTH RELEVANCE: Lung transplantation is usually the only option for patients with irreversible structural lung damage but is hindered by major obstacles such as lack of lung organ donors and chronic rejection. We will focus on rebuilding the lung using ventilated, decellularized whole rodent lungs as a natural 3-D matrix and repopulate it with cells having the potential to grow into lung tissue and produce proteins characteristic of lung cells.

描述（由申请人提供）：我们的最终目标是使用脱细胞肺作为肺祖细胞的天然3维（3-D）基质碱基重建肺。肺移植通常是不可逆的结构性肺损伤患者的唯一选择，但受到主要障碍（例如缺乏肺部器官供体和慢性排斥反应）的主要障碍。人造脚手架不能复制肺部细胞外基质的分支，排列和拉伸。我们将专注于使用通风的，脱细胞的全肺作为天然3-D基质来重建肺，并以具有肺上皮和内皮祖细胞潜力的细胞重新填充。我们有数据，即即使在延长通气后，啮齿动物肺也可以成功地脱细胞，同时保持细胞外基质的状态。成年和胎儿肺细胞可以成功地注入并培养在脱细胞的通风肺中。我们假设，鉴于正确的生长条件，推定的祖细胞将重新上皮化并重新内皮化基质并产生肺部细胞的蛋​​白质特征。我们还期望细胞输入，生长因子和适当阶段的通气时间的时机对此过程至关重要。在AIM 1中，我们将确定假定的肺祖细胞群（例如诱导的多能（IPS）细胞，BM衍生的细胞和EPCAM+肺衍生的细胞）是否会在我们的“ new new bioreactor”系统中生长和区分。我们将在成年和胎儿肺制备的脱细胞基质中单独和组合培养这些细胞。在AIM 2中，我们将确定上皮和内皮是否可以使用血液生长的内皮细胞（BOEC）和AIM 1的最佳细胞进行覆盖。我们处于执行这些研究的独特位置。我们有一个独特的模型系统和经验丰富的合作者，他们为该赠款应用提供新颖的细胞，重要的专业知识和建议。 公共卫生相关性：通常，肺移植是不可逆的结构性肺损害的唯一选择，但受到诸如缺乏肺部器官捐献者和慢性拒绝等主要障碍的阻碍。我们将专注于使用通风的，脱细胞的整个啮齿动物肺作为天然3-D基质来重建肺，并以具有生长成肺组织并产生肺细胞的蛋白质的细胞来重新填充它。