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Loss of centrosomal gene ALMS1 alters lipid metabolism and the regulation of processes linked to the extracellular matrix.

ABSTRACT: In this project we evaluated the proteomic profiling with TGF-β stimuli at 24h in a CRISPR-Cas9 model for ALMS1 gene in hTERT-BJ-5ta cells. Proteomic results showed a majority inhibition of downstream regulated pathways by the TGF-β, associating the protein coding genes (PCG) with processes like TGF- β matrix regulation, epithelial mesenchymal transition (EMT), PI3K/AKT or P53. In conclusion, seems that the depletion of ALMS1 could be inhibiting the signals transduction through the TGF -β and the routes regulated downstream.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Erythrocyte, Cell Culture

DISEASE(S): Ciliopathy

SUBMITTER: Brais Bea Mascato

LAB HEAD: Brais Bea-Mascato

PROVIDER: PXD035708 | Pride | 2024-01-26

REPOSITORIES: Pride

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Loss of the centrosomal protein ALMS1 alters lipid metabolism and the regulation of extracellular matrix-related processes.

Bea-Mascato Brais B Gómez-Castañeda Eduardo E Sánchez-Corrales Yara E YE Castellano Sergi S Valverde Diana D

Biology direct 20231208 1

<h4>Background</h4>Alström syndrome (ALMS) is a rare autosomal recessive disease that is associated with mutations in ALMS1 gene. The main clinical manifestations of ALMS are retinal dystrophy, obesity, type 2 diabetes mellitus, dilated cardiomyopathy and multi-organ fibrosis, characteristic in kidneys and liver. Depletion of the protein encoded by ALMS1 has been associated with the alteration of different processes regulated via the primary cilium, such as the NOTCH or TGF-β signalling pathways ...[more]

PMID: 38062477

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Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individualÂ¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while gene expression was profiled in the adjacent sample from the same region using the Affymetrix Human Exon 1.0 ST GeneChip. Human fibroblast cell lines (HLF-1) were treated with GHK or TGF-Beta1 for 48 hours and profiled using the Affymetrix Human Gene 1.0 ST GeneChip.

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