Epithelial wound healing in 3 dimensions

三维上皮伤口愈合

• 批准号: 7556197
• 负责人: Keith E Mostov
• 金额: $ 73.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7556197
• 关键词: 3-Dimensional; Acute; Acute Lung Injury; Address; Alveolar; Annexins; Anthrax disease; Biological Models; Biological Warfare; Bronchial Tree; Canis familiaris; Cell Communication; Cell Death; Cell Line; Cell Polarity; Cell model; Cells; Collaborations; Collagen; Condition; Cyst; Dimensions; Disruption; Enzymes; Epithelial; Epithelial Cells; Extracellular Matrix; Gel; Genitourinary system; Green Fluorescent Proteins; HIV; Healed; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hepatocyte Growth Factor; Human; Hydrolase; Image; Immune system; Infection; Infectious Agent; Inflammation; Inhibition of Matrix Metalloproteinases Pathway; Injury; Inorganic Sulfates; Integrins; Kidney; Life; Lipids; Lung; MDCK cell; Matrix Metalloproteinases; Methods; Modeling; Molecular; Morphogenesis; Newborn Respiratory Distress Syndrome; Opportunistic Infections; Organ; PTEN gene; PTEN protein; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Process; Pseudomonas aeruginosa; Pseudostratified Epithelium; Respiratory System; Role; Secondary to; Sexually Transmitted Diseases; Smallpox; Staging; Structure of respiratory epithelium; Sulfatases; Surface; System; Testing; Tissues; Trauma; Tube; Unspecified or Sulfate Ion Sulfates; Work; Wound Healing; Yersinia pestis; alveolar type II cell; cell behavior; defense response; gastrointestinal; healing; in vivo; matrigel; monolayer; pathogen; repaired; respiratory; response; response to injury

Greater than 95% of infectious agents enter through exposed mucosal surfaces, such as the respiratory, gastrointestinal and genitourinary tracts. These include HIV, sexually transmitted diseases, numerous opportunistic infections, TB, many emerging and re-emerging infections, and biological warfare/terrorist agents, such as anthrax, Yersinia pestis and small pox. Most mucosal surfaces are lined by a monolayer of polarized epithelial cells, which forms the principal barrier to entry by infectious agents. In essence, the epithelial layer can be considered the most basic component of the innate mucosal immune system. Some pathogens cross the epithelial layer by disrupting it. Other pathogens exploit disruptions in the monolayer, which can be caused by tissue injury secondary to inflammation, trauma, or may result from cell death or division within the monolayer. To maintain their function as a barrier to infection, epithelial tissues have developed efficient wound healing mechanisms. Wound healing is central to mucosal defense against infection. The epithelial barrier must be restored as quickly as possible, to minimize the opportunity for entry of infectious agents. Some infectious agents, such as Pseudomonas aeruginosa, not only exploit pre-existing wounds, but also impede the wound healing process. We are studying epithelial wound healing by growing epithelial cells in 3 dimensional cultures of extracellular matrix, which causes the cells to more closely resemble in vivo conditions. In Aim 1 we are using a system of human primary lung alveolar type II cells, which form alveolar-like cysts, as a model to study response to acute lung injury/acute respiratory distress syndrome. In Aim 2, we are using a three-dimensional system of a well-differentiated human airway cell line, which forms cysts and tubules lined by pseudostratified epithelium, as a model to study airway response to injury. In Aim 3 we are studying the roles of matrix metalloproteinases and sulfatases (enzymes that remove 6-O-sulfate groups from heparan sulfate proteoglycans) in our three dimensional culture systems. This work will be in collaboration with Projects 2, 3 and 4, and supported by Cores B and C. Most infectious agents enter through the layer of cells that lines internal organs, such as the lung. Injuries to this cell layer makes it much easier for pathogens to enter and we are studying how the cell layer heals itself.

超过 95% 的感染因子通过暴露的粘膜表面进入，例如 呼吸道、胃肠道和泌尿生殖道。其中包括艾滋病毒、性传播疾病、 许多机会性感染、结核病、许多新出现和重新出现的感染以及生物感染 战争/恐怖分子，例如炭疽、鼠疫耶尔森菌和天花。大多数粘膜表面衬有 单层极化上皮细胞，形成感染因子进入的主要屏障。在 本质上，上皮层可以认为是先天性粘膜免疫的最基本组成部分 系统。一些病原体通过破坏上皮层来穿过它。其他病原体利用破坏 单层细胞，可能是由炎症、创伤继发的组织损伤引起的，也可能是由于 单层细胞死亡或分裂。为了维持其作为感染屏障的功能，上皮细胞 组织已经发展出有效的伤口愈合机制。伤口愈合是粘膜防御的核心 防止感染。上皮屏障必须尽快恢复，以尽量减少机会 用于传染性病原体的进入。一些传染性病原体，例如铜绿假单胞菌，不仅利用 预先存在的伤口，还会阻碍伤口的愈合过程。我们正在研究上皮伤口愈合 通过在细胞外基质的 3 维培养物中生长上皮细胞，这会导致细胞更多 与体内条件非常相似。在目标 1 中，我们使用人类原发肺 II 型肺泡系统 细胞，形成肺泡样囊肿，作为研究急性肺损伤/急性呼吸道反应的模型 苦恼综合症。在目标 2 中，我们使用分化良好的人类气道的三维系统 细胞系，形成由假复层上皮排列的囊肿和小管，作为研究气道的模型 对伤害的反应。在目标 3 中，我们正在研究基质金属蛋白酶和硫酸酯酶（酶 在我们的三维培养物中去除硫酸乙酰肝素蛋白聚糖中的 6-O-硫酸基团） 系统。这项工作将与项目 2、3 和 4 合作，并得到核心 B 和 C 的支持。 大多数传染源通过内脏器官（例如肺）的细胞层进入。 该细胞层的损伤使病原体更容易进入，我们正在研究细胞层如何 自愈。