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Role of alveolar fibroblasts in extracellular matrix organization and alveolar type 1 cell differentiation

肺泡成纤维细胞在细胞外基质组织和肺泡1型细胞分化中的作用

基本信息

批准号：
10731854
负责人：
Anne-Karina Theresia Perl
金额：
$ 80.01万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731854
关键词：
Address Adhesions Adult Alveolar Alveolus Animal Model Basal Cell Basal lamina Binding Biological Assay Bronchopulmonary Dysplasia Cell Communication Cell Differentiation process Cell Proliferation Cells ChIP-seq Characteristics Chromatin Chronic lung disease Collagen Data Data Set Deposition Development Dysplasia EZH2 gene Engraftment Epigenetic Process Epithelial Cells Epithelium Extracellular Matrix Fibroblasts Fibrosis Future GATA6 transcription factor Gene Expression Genes Genetic Genetic Transcription Genomics Goals Homeostasis Human Hyperoxia Hyperplasia Impairment In Vitro Infant Knowledge Lipids Lung Lung diseases Membrane Mission Modeling Modification Molecular Mus Natural regeneration Nature Nuclear Organoids Paracrine Communication Patients Perinatal Population Premature Infant Proteomics Public Health Pulmonary Emphysema Regulation Regulatory Element Replacement Therapy Reporting Repression Reproducibility Research Role Signal Transduction Site Specific qualifier value Structure Testing Tissues Transcriptional Regulation United States National Institutes of Health WNT Signaling Pathway alveolar epithelium cofactor comparative experimental study fibroblast growth factor 18 fibrotic lung disease gain of function idiopathic pulmonary fibrosis in vitro Model induced pluripotent stem cell inhibitor innovation insight intercellular communication loss of function lung injury lung regeneration overexpression paracrine perinatal period permissiveness pharmacologic postnatal promoter regenerative therapy repaired restoration self-renewal small hairpin RNA therapy development tool transcription factor transcriptomics transdifferentiation

项目摘要

ABSTRACT: An in-depth understanding of the mechanisms that regulate alveolar septation and septal wall maturation will be required to develop therapies for premature infants with Bronchopulmonary Dysplasia (BPD) and for developing potential therapies for adult lung regeneration. We and others have begun to define changes in PDGFRa myo, lipo and matrix fibroblast (FB) function during alveolarization, homeostasis, regeneration, and fibrosis. Our long-term goal is elucidation of molecular regulators of FB functions and how diverse FBs support epithelial cells. Our objective herein is to identify molecular mech- anisms that result in functional changes in alveolar fibroblasts that regulate ECM organization and epithelial differentia- tion. Integration of transcriptomic datasets predicted GATA6 as a regulator of PDGFRa-FB differentiation. Our preliminary data show that conditional inactivation of GATA6 in perinatal PDGFRa+ FBs resulted in loss of matrix and gain in lipo fibro- blast function comparable to findings in BPD and animal models of hyperoxia. GATA6 inactivation in PDGFRa+ FBs also resulted in fragmented collagen and detachment of AT1 cells from the basal lamina demonstrating a thus far unidentified role of alveolar FBs in ECM organization. Inactivation of GATA6 resulted in significant increase of the lipo FB transcription factor TCF21 expression and preliminary in vitro data suggest suppression of TCF21 by GATA6. The central hypothesis is that GATA6 and transcriptional cofactors regulate FB function in alveolar FBs by suppressing lipo FB differentiation. The rationale for this research is a new understanding of the regulation of matrix FB function and how these functionally different stages modify extracellular matrix and the FB-epithelial crosstalk. Aim 1 will test the hypothesis that GATA6 suppresses lipo FB function and promotes ECM deposition in the alveolar FBs. This aim will use lineage tracing to deter- mine trans-differentiation of the alveolar FB to a lipo FB. And use in vitro cell derived matrices to identify ECM modifica- tions by lipo and matrix FBs. Aim 2 will test the hypothesis that GATA6 is in a transcriptional network that regulates lipo and matrix FB function. In this aim we will use in vitro gain and loss of function of GATA6 and TCF21 and identify and validate transcriptional networks and partnering transcription factors. Aim 3 will test the hypothesis that GATA6 regulates ECM synthesis and paracrine signaling in PDGFRa+ FBs that direct AT2 to AT1 differentiation. The proposed studies in this application will identify the transcriptional regulation of matrix FB function and their role in extracellular matrix deposition and cell-cell signaling in the alveolar niche. The proposed research is conceptually innovative, because we ask questions regarding the nature of fibroblast plasticity and functional switches. The proposed research is scientifically innovative, because the contractile function of alveolar fibroblasts, has been thoroughly investigated, but little is known about their matrix organizing function or their role in supporting AT2 proliferation and AT1 differentiation This contribution will be significant because it addresses 1) lack of knowledge of matrix and signaling function of the alveolar FB; 2) identifies and validates the transcriptional network around GATA6 that regulates FB function.