2016 — 2020 |
Chen, Jichao |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of At1 Cells in Perinatal Lung Maturation @ University of Tx Md Anderson Can Ctr
? DESCRIPTION (provided by applicant): Perinatal lung maturation allows transition to independent extrauterine life and requires concerted expansion of the epithelial gas exchange surface and the juxtaposed capillaries. Interruption of this process by premature birth is a major risk factor for serious lung diseases, such as bronchopulmonary dysplasia (BPD) that frequently manifests as alveolar simplification and dysmorphic capillaries. Although covering >95% of the alveolar surface and overlaying most of the alveolar vasculature, alveolar type 1 (AT1) cells are traditionally considered a passive structural component and attention has been focused on alveolar type 2 (AT2) cells because of their stem cell potential and role in surfactant production. This, combined with technical challenges in studying the ultra-thin (<0.1 um) AT1 cell extensions, results in our limited knowledge of the role of AT1 cells in normal and pathological alveologenesis. An in-depth understanding of AT1 cells during development is necessary to catch up with recent progress in studying AT2 cells and fibroblasts to obtain a complete picture of perinatal lung maturation. Our preliminary data support a novel hypothesis that AT1 cells have a signaling role in coordinating alveolar morphogenesis and angiogenesis during perinatal lung maturation. This proposal has the following three specific aims. (1) To determine whether AT1 cell development promotes alveolar angiogenesis. (2) To determine whether AT1 cell derived angiogenic factors promote alveolar angiogenesis. (3) To determine whether AT1 cell dysfunction contributes to hyperoxia-induced alveolar simplification. In summary, this proposal employs novel quantitative imaging and genetic tools to study the poorly understood and unexpected role of AT1 cells in perinatal lung maturation, and represents a step toward our long term goal of elucidating mechanisms and therapies of lung immaturity.
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0.939 |
2020 — 2021 |
Chen, Jichao |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Transcriptional and Epigenetic Basis of Lung Epithelial Cell Fate @ University of Tx Md Anderson Can Ctr
PROJECT SUMMARY The lung epithelium consists of diverse cell types, as the result of embryonic progenitors undergoing a series of precise cell fate decisions. Upon injury, a successful repair needs to restore the proper cell fates. Recapitulation and modulation of in vivo cell fate biology holds promise for cell-based regeneration therapy. Despite such fundamental importance and our accumulating knowledge of cell fate regulators, the epigenetic basis of lung cell fate ? defined in this proposal as chromatin state and its relationship to transcription factor binding ? is largely unknown, but essential for mechanistic understanding of cell fate regulators. Combining mouse genetics, genomics of both purified bulk and single cells, 3D imaging, and human stem cell technology, this proposal will test our central hypothesis that sequential and combinatorial actions of NKX2-1 and Wnt signaling transcription factors control the epigenetic maturation and maintenance of lung epithelial cell types in vivo. The proposal has the following 3 aims. (1) To test whether lung fate maintenance shifts from Wnt-dependent to NKX2-1 self- reinforcing as the lung matures. (2) To test whether NKX2-1 promotes AT1 versus AT2 cell fate as a result of recruitment by YAP/TAZ/TEAD versus CEBPA, respectively. (3) To test whether NKX2-1 primes AT2 cells for AT1 differentiation.
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0.939 |
2021 |
Chen, Jichao |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Mesenchymal Cells by Epithelial Wnt Ligands @ University of Tx Md Anderson Can Ctr
PROJECT SUMMARY Alveologenesis requires co-development of the epithelium, mesenchyme, and vasculature, the failure of which is a cardinal feature of bronchopulmonary dysplasia (BPD). This process depends on precisely controlled intercellular signaling, such as Fgf, Pdgf, Shh, and Vegf signaling, as revealed by recent work including ours in the previous grant period. Another major signaling pathway, Wnt signaling, extensively studied in embryonic lungs and potentially involved in adult lungs, is poorly understood in the neonatal period. Moreover, published Wnt studies focus on epithelial cells, but largely ignore the robust expression of Wnt target genes within the postnatal mesenchyme. Further contributing to our limited understanding of mesenchymal Wnt signaling is lack of clarity on the cell types in the mesenchyme, which starts to be unveiled via single-cell genomics. By following the unexpected signaling role of AT1 cells in the previous grant period, we have obtained evidence that epithelial WNT ligands specifically signal toward myofibroblasts during alveologenesis. Pursuing, as proposed, the signaling cells (Aim 1), the receiving cells (Aim 2), and the disease relevance (Aim 3) is expected to not only elucidate the little-known mesenchymal Wnt signaling, but also establish an experimental paradigm applicable to future lung mesenchyme research.
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0.939 |