Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA377202 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Multicenter International Retrospective Cross-sectional Evaluation of Pulmonary Alveolar Proteinosis (MICEPAP) Trial - RLD 5706
| PRJNA377201 | ENA
Project description:To uncover potential mechanisms underlying the observed Pulmonary Alveolar Proteinosis-like phenotype, we performed a microarray analysis using lung mRNAs from T-bet transgenic mice. Gene expression signatures associated with pulmonary alveolar proteinosis induced by T-bet overexpression in T cells were measured.
2014-11-03 | E-GEOD-62637 | biostudies-arrayexpress
Project description:Isoleucyl-tRNA synthetase 1(IARS1) disorder is a recently identified multi-organ disease, only a limited cases have been reported so far; furthermore, the mechanisms underlying IARS1 mutation and the symptoms remain unknown. In this report, we present four families with seven distinct IARS1 variants, associated with growth retardation, fatty liver, mental development disorder, and severe pulmonary alveolar proteinosis. IARS1-Tyr148Cys/Arg444* mice are established and exhibited pulmonary alveolar proteinosis and other multi-organ disorders that closely mimic human phenotype. Analysis of single cell RNA sequencing of peripheral blood mononuclear cells from patients and lung metabolomics of lung in IARS1-Tyr148Cys/Arg444* mice analysis indicated disruption in phagosome, lysosome and fatty acid metabolism, cholesterol metabolism pathways. IARS1 mutations results in accumulation of surfactant in alveolar macrophages and alveoli in compound heterozygous mouse model, while IARS1 deficiency impairs the post-translation of Cathepsin Z(CTSZ) by inhibiting ubiquitin-mediated degradation. CTSZ depleted also shows abnormal cholesterol degradation and deposition of pulmonary surfactant associated proteins and overexpression CTSZ could rescue IARS1 deficiency related alveolar macrophage disfunction in vitro. These finding suggest that biallelic IARS1 deficiency impair alveolar macrophage, partly by impair CTSZ -dependent degeneration; and IARS1 could consider as a candidate gene in inherit pulmonary alveolar proteinosis.
2025-12-01 | GSE250411 | GEO
Project description:Isoleucyl-tRNA synthetase 1(IARS1) disorder is a recently identified multi-organ disease, only a limited cases have been reported so far; furthermore, the mechanisms underlying IARS1 mutation and the symptoms remain unknown. In this report, we present four families with seven distinct IARS1 variants, associated with growth retardation, fatty liver, mental development disorder, and severe pulmonary alveolar proteinosis. IARS1-Tyr148Cys/Arg444* mice are established and exhibited pulmonary alveolar proteinosis and other multi-organ disorders that closely mimic human phenotype. Analysis of single cell RNA sequencing of peripheral blood mononuclear cells from patients and lung metabolomics of lung in IARS1-Tyr148Cys/Arg444* mice analysis indicated disruption in phagosome, lysosome and fatty acid metabolism, cholesterol metabolism pathways. IARS1 mutations results in accumulation of surfactant in alveolar macrophages and alveoli in compound heterozygous mouse model, while IARS1 deficiency impairs the post-translation of Cathepsin Z(CTSZ) by inhibiting ubiquitin-mediated degradation. CTSZ depleted also shows abnormal cholesterol degradation and deposition of pulmonary surfactant associated proteins and overexpression CTSZ could rescue IARS1 deficiency related alveolar macrophage disfunction in vitro. These finding suggest that biallelic IARS1 deficiency impair alveolar macrophage, partly by impair CTSZ -dependent degeneration; and IARS1 could consider as a candidate gene in inherit pulmonary alveolar proteinosis.
2025-12-01 | GSE250270 | GEO
Project description:To uncover potential mechanisms underlying the observed Pulmonary Alveolar Proteinosis-like phenotype, we performed a microarray analysis using lung mRNAs from T-bet transgenic mice.
2014-11-03 | GSE62637 | GEO
Project description:Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain largely elusive. Here, through a genome-wide CRISPR activation screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify Deltex E3 Ubiquitin Ligase 4 (DTX4) as a pivotal regulator of cholesterol efflux in AMs. Adeno-associated virus (AAV) -mediated silencing of DTX4 led to excessive lipid accumulation in AMs, exacerbated alveolar proteinosis, increased lung opacities on imaging, and significantly deteriorated pulmonary function in mice. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. In contrast, AM-specific overexpression of DTX4 markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities on computed tomography, and rescued pulmonary function in Csf2ra-/-mice, a model of PAP. Mechanistically, DTX4 deficiency downregulated PPAR-γ expression, driving foamy AM formation. Notably, the regulatory function of DTX4 in lipid homeostasis was partially mediated by PPAR-γ but independent of its canonical E3 ubiquitin ligase activity. Collectively, our findings establish DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP and a potential paradigm for cholesterol dysregulation in related disorders.
2026-04-23 | GSE299696 | GEO
Project description:Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain largely elusive. Here, through a genome-wide CRISPR activation screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify Deltex E3 Ubiquitin Ligase 4 (DTX4) as a pivotal regulator of cholesterol efflux in AMs. Adeno-associated virus (AAV) -mediated silencing of DTX4 led to excessive lipid accumulation in AMs, exacerbated alveolar proteinosis, increased lung opacities on imaging, and significantly deteriorated pulmonary function in mice. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. In contrast, AM-specific overexpression of DTX4 markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities on computed tomography, and rescued pulmonary function in Csf2ra-/-mice, a model of PAP. Mechanistically, DTX4 deficiency downregulated PPAR-γ expression, driving foamy AM formation. Notably, the regulatory function of DTX4 in lipid homeostasis was partially mediated by PPAR-γ but independent of its canonical E3 ubiquitin ligase activity. Collectively, our findings establish DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP and a potential paradigm for cholesterol dysregulation in related disorders.
2026-04-23 | GSE299693 | GEO
Project description:Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain largely elusive. Here, through a genome-wide CRISPR activation screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify Deltex E3 Ubiquitin Ligase 4 (DTX4) as a pivotal regulator of cholesterol efflux in AMs. Adeno-associated virus (AAV) -mediated silencing of DTX4 led to excessive lipid accumulation in AMs, exacerbated alveolar proteinosis, increased lung opacities on imaging, and significantly deteriorated pulmonary function in mice. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. In contrast, AM-specific overexpression of DTX4 markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities on computed tomography, and rescued pulmonary function in Csf2ra-/-mice, a model of PAP. Mechanistically, DTX4 deficiency downregulated PPAR-γ expression, driving foamy AM formation. Notably, the regulatory function of DTX4 in lipid homeostasis was partially mediated by PPAR-γ but independent of its canonical E3 ubiquitin ligase activity. Collectively, our findings establish DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP and a potential paradigm for cholesterol dysregulation in related disorders.
2026-04-23 | GSE299689 | GEO
Project description:The potential importance of menin in immune regulation remains unclear. Here, we report that myeloid deletion of Men1 results in the development of spontaneous pulmonary alveolar proteinosis (PAP). This is strongly correlated with impaired development of alveolar macrophages (AM) and epigenetic inactivation of the GM-CSF pathway caused by Men1 deficiency. Mechanistically, menin directly interacts with SETD2 and collectively maintain GM-CSF expression through H3K36me3, which orchestrates AM reprogramming and pulmonary immune homeostasis.
2024-12-25 | GSE240958 | GEO
Project description:Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial) - RLDC 5702
| PRJNA189546 | ENA