Jichao Chen
副教授
德克萨斯大学医学博士安德森癌症中心
Departments of Pulmonary Medicine
我的实验室对建立肺部的正常发育过程以及在肺部畸形，损伤和肿瘤发生过程中的出现感兴趣。我的实验室的独特之处在于，我们努力开发一系列三维标签和成像方法，例如光投影层析成像。我们开发了这些新颖的方法来解决研究肺部的重大挑战 - 其复杂的三维结构，包括树状气道和类似蜂窝状的肺泡，使得很难在常规的二维部分上比较结构。
Development of the alveolar type 1 cell and bronchopulmonary dysplasia
Bronchopulmonary dysplasia (BPD) is a major chronic lung disease associated with preterm birth and characterized by alveolar simplification with dysmorphic microvasculature. Current BPD research focuses on myofibroblasts, alveolar type 2 (AT2) cells and the endothelium, but seems to leave out the “elephant in the room”, the alveolar type 1 (AT1) cell, which constitutes nearly all the alveolar surface and associates intimately with the microvasculature. We have delineated a two-step AT1 cell morphogenesis process, cell flattening and cell folding, which leads to its ultrathin and yet expansive morphology. We have identified a key transcriptional regulator of this process, without which AT1 cells lose their molecular and cellular characteristics and the lung undergoes alveolar simplification as in BPD. Thus, our findings have implicated AT1 cell development and its regulator in the pathogenesis of BPD. We are dissecting the direct and indirect targets of this regulator. We are also interested in its role in AT1 cell homeostasis and injury in the adult lung.
肺泡1型细胞的新型信号传导作用
传统上，AT1细胞被认为是肺泡的被动结构成分，而由于提出的干细胞功能，注意力集中在AT2细胞上。我们发现，AT1细胞而不是AT2细胞是关键血管生成因子VEGFA的意外来源，而AT1细胞衍生的VEGFA是肺泡血管生成所必需的。这些发现打开了对肺泡血管生成的机械理解的大门，肺泡血管生成是通过肠use脚的血管生成发生的，但在分子和细胞水平上却鲜为人知。我们正在研究肺部内皮细胞在肠胃s依性的血管生成过程中如何对VEGFA反应，以及在特征良好的视网膜发芽血管生成过程中，相同的VEGFA信号是否与相同的VEGFA信号引起不同的反应。我们还对稳态和肿瘤发生过程中AT1细胞衍生的VEGFA的作用感兴趣。
鉴于我们证明了AT1细胞及其广泛的表面积的意外血管生成作用，我们假设AT1细胞具有其他新型的信号传导作用。通过一系列转录组分析，我们已经确定了在AT1细胞而不是AT2细胞中特异性表达的Wnt配体，这种表达模式与VEGFA相似。我们已经产生了条件敲除等位基因，以测试AT1细胞是否也可能发出向间充质细胞（例如肌纤维细胞）的信号。
Maintenance of airway cell mosaicism during growth and regeneration
肺部通过粘膜纤毛清除过滤了吸入的空气，其失败鼓励微生物生长和炎症，如哮喘和COPD中。粘膜钙清除功能在之间分配，因此需要对两种气道细胞类型（分泌和纤毛细胞）进行协调，分泌细胞的分泌细胞被秘密粘液捕获吸入的微生物和颗粒，而纤毛细胞则通过输送机皮带样作用移动粘液层。这种功能协调取决于分泌和纤毛的细胞，并以适当的比例和模式相结合，我们称之为气道细胞镶嵌物。这种气道细胞镶嵌物是在胚胎发育过程中在Notch信号传导下建立的，但必须在随后的气道生长期间保持并在再生过程中重新建立。结合了克隆分析，整个安装成像和计算建模，我们找到了一种证据，证明了维持气道细胞镶嵌物的强大自我校正机制。我们正在开发一种新型的体细胞CRISPR方法，以剖析潜在的分子机制。我们还有兴趣将分析扩展到具有第三个气道细胞类型基底细胞的更复杂的气管上皮。
A hierarchical gene regulatory network controlling SOX9 epithelial progenitors
We have shown that the entire lung epithelium arises from a group of SOX9 epithelial progenitors. The SOX9 progenitors emerge as the lung primordium just buds off the embryonic foregut, constitute all the tips of the rapidly-branching respiratory tree, and disappear soon after birth as the alveolar region matures. Lineage tracing shows that they differentiate into SOX2 airway cells during early development and alveolar cells during late development. Thus, the maintenance and differentiation of the SOX9 progenitors must be precisely controlled in coordination with branching morphogenesis and developmental timing. Although a number of signaling pathways have been identified to affect the SOX9 progenitors, it is unclear how different signaling pathways interact and what molecular changes they elicit in the SOX9 progenitors. We hypothesize a hierarchical gene regulatory network shapes the epigenetic landscape of the SOX9 progenitors to control their maintenance and differentiation. Using genetic epistasis analysis and genomic bioinformatics, we have assembled an initial gene regulatory network and are developing methods to assay the epigenome of purified SOX9 progenitors. We believe that perturbation or modulation of the gene network in the SOX9 progenitors underlies abnormal/sub-optimal lung development or species-specific lung branching complexity, respectively.
教育和培训
PhD, Johns Hopkins University School of Medicine, 2006
Research Info
lung development; organ size control; lung cancer