Miquéias Lopes‐Pacheco

University of Lisbon

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Patrícia R. M. Rocco

Universidade Federal do Rio de Janeiro

Marcelo M. Morales

Universidade Federal do Rio de Janeiro

Margarida D. Amaral

University of Lisbon

Débora G. Xisto

Universidade Federal do Rio de Janeiro

Fernanda F. Cruz

Universidade Federal do Rio de Janeiro

Mafalda Bacalhau

University of Lisbon

Johnatas D. Silva

Queen's University Belfast

Lígia Lins de Castro

Universidade Federal do Rio de Janeiro

Jamil Z. Kitoko

Instituto Gulbenkian de Ciência

Bianca Gutfilen

Hospital Universitário Clementino Fraga Filho

Cooperative Institutions

Universidade Federal do Rio de Janeiro

135

Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

National Institute of Science and Technology in Regenerative Medicine

Universidade de São Paulo

Hospital Universitário Clementino Fraga Filho

University of Toronto

Fundação Oswaldo Cruz

Czech Academy of Sciences, Institute of Biophysics

University of Lisbon

Instituto de Biofísica Carlos Chagas Filho

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

"Global Functional Genomics Reveals GRK5 as a Therapeutic Target for Cystic Fibrosis", CFTR interactomes

Zenodo (CERN European Organization for Nuclear Research) (2022)

Hugo M. Botelho Miquéias Lopes‐Pacheco Madalena C. Pinto Luka A. Clarke Vasco Cachatra

A tidy selection of published CFTR interactomes (or CFTR-related omics datasets) Collects data from the original online sources, converts gene/protein identifiers into a standard tidy format and updates the identifiers. The Uniprot ID is taken as reference and all other identifiers are genereated from them. This causes some datasets to end up with less genes/proteins than reported. Datasets included Botelho (2021) - CFTR traffic regulators Botelho et al (2022), submitted Pankow (2015) - CFTR interactome Pankow et al (2015) deltaF508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature. 528, 510--516. https://doi.org/10.1038/nature15729 Canato (2018) - CFTR interactome Canato et al (2018) Proteomic interaction profiling reveals KIFC1 as a factor involved in early targeting of F508del-CFTR to degradation. Cell Mol Life Sci. 75(24):4495-4509. https://doi.org/10.1007/s00018-018-2896-7 Santos (2019) - CFTR interactome Santos et al (2019) Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum. Cells. 8(4):353. https://doi.org/10.3390/cells8040353 Hutt (2018) - CFTR interactome Hutt et al (2018) A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease. J Mol Biol. 430: 2951-2973. https://doi.org/10.1016/j.jmb.2018.06.017 Rauniyar (2014) - CFTR proteome Rauniyar et al (2014) Quantitative Proteomic Profiling Reveals Differentially Regulated Proteins in Cystic Fibrosis Cells. J Proteome Res. 13(11): 4668-4675. https://doi.org/10.1021/pr500370g Almaça (2013) - ENaC regulome Almaça et al (2013) High-content siRNA screen reveals global ENaC regulators and potential cystic fibrosis therapy targets. Cell. 154(6):1390-400. https://doi.org/10.1016/j.cell.2013.08.045 Tomati (2018) - CFTR regulome Tomati et al (2018) High-throughput screening identifies FAU protein as a regulator of mutant cystic fibrosis transmembrane conductance regulator channel. J Biol Chem. 293(4):1203-1217. https://doi.org/10.1074/jbc.m117.816595 Simpson (2012) - Secretome Simpson et al (2012) Genome-wide RNAi screening identifies human proteins with a regulatory function in the early secretory pathway. Nature Cell Biology. 14, 764-774. https://doi.org/10.1038/ncb2510 Wang (2006) - CFTR interactome Wang et al (2006) Hsp90 Cochaperone Aha1 Downregulation Rescues Misfolding of CFTR in Cystic Fibrosis. Cell. 127(4):803-815. https://doi.org/10.1016/j.cell.2006.09.043 Reilly (2017) - CFTR interactome Reilly et al (2017) Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis. Sci Rep. 9;7(1):7642. https://doi.org/10.1038/s41598-017-06588-z Gilchrist (2006) - Secretome Gilchrist et al (2006) Quantitative Proteomics Analysis of the Secretory Pathway. Cell. 127(6):1265-1281. https://doi.org/10.1016/j.cell.2006.10.036 Pankow (2019) - CFTR interactome Pankow et al (2019) A posttranslational modification code for CFTR maturation is altered in cystic fibrosis. Science Signaling. 12(562):eaan7984. https://doi.org/10.1126/scisignal.aan7984 Dang (2020) - CF lung disease modifier genes Dang et al (2020) Mining GWAS and eQTL data for CF lung disease modifiers by gene expression imputation. PLoS One. 15(11):e0239189. https://doi.org/10.1371/journal.pone.0239189 Hodos (2020) - CF genomic meta-analysis Hodos et al (2020) Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and deltaF508-CFTR rescue. Sci Rep 10(1):20553. http://dx.doi.org/10.1038/s41598-020-76347-0

Functional Genomics

10.5281/zenodo.6646235

Cite

Citations (0)

Global Functional Genomics Reveals GRK5 as a Therapeutic Target for Cystic Fibrosis

Zenodo (CERN European Organization for Nuclear Research) (2022)

Hugo M. Botelho Miquéias Lopes‐Pacheco Madalena C. Pinto Luka A. Clarke Vasco Cachatra

Cystic Fibrosis (CF) is a life-shortening disease affecting >90,000 individuals worldwide predominantly with respiratory symptoms. About 80% of individuals with CF have the F508del mutation that causes the CF transmembrane conductance regulator (CFTR) protein to misfold and be targeted for premature degradation by the endoplasmic reticulum (ER) quality control (ERQC), thus preventing its plasma membrane (PM) traffic. Despite the recent approval of a ‘highly effective’ drug rescuing F508del-CFTR, maximal lung function improvement is ~14% and the drug-targeted genes remain unknown. To identify global modulators of F508del traffic, we performed a high-content siRNA microscopy-based screen of >9,000 genes and monitored F508del-CFTR PM rescue in human airway cells. This primary screen identified 227 F508del-CFTR traffic regulators, of which 35 could be validated by additional siRNAs. Subsequent mechanistic studies established GRK5 as a robust regulator whose inhibition rescues F508del-CFTR PM traffic, thus emerging as a novel potential drug target for CF.

10.5281/zenodo.6617739

Cite

Citations (0)

Self-complementary and tyrosine-mutant rAAV vectors enhance transduction in cystic fibrosis bronchial epithelial cells

Experimental Cell Research (2018)

Miquéias Lopes‐Pacheco Jamil Z. Kitoko Marcelo M. Morales Hilda Petrs‐Silva Patrícia R. M. Rocco

Transduction (biophysics)

Adeno-associated virus

10.1016/j.yexcr.2018.09.015

Cite

Citations (7)

Repeated Administration of Bone Marrow-Derived Cells Prevents Disease Progression in Experimental Silicosis

Cellular Physiology and Biochemistry (2013)

Miquéias Lopes‐Pacheco Débora G. Xisto Felipe M. Ornellas Mariana A. Antunes Soraia C. Abreu

Background/Aims: Bone marrow-derived cells (BMDCs) reduced mechanical and histologic changes in the lung in a murine model of silicosis, but these beneficial effects did not persist in the course of lung injury. We hypothesized that repeated administration of BMDCs may decrease lung inflammation and remodeling thus preventing disease progression. Methods: One hundred and two C57BL/6 mice were randomly divided into SIL (silica, 20 mg intratracheally [IT]) and control (C) groups (saline, IT). C and SIL groups were further randomized to receive BMDCs (2×106 cells) or saline IT 15 and 30 days after the start of the protocol. Results: By day 60, BMDCs had decreased the fractional area of granuloma and the number of polymorphonuclear cells, macrophages (total and M1 phenotype), apoptotic cells, the level of transforming growth factor (TGF)-β' and types I and III collagen fiber content in the granuloma. In the alveolar septa, BMDCs reduced the amount of collagen and elastic fibers, TGF-β, and the number of M1 and apoptotic cells. Furthermore, interleukin (IL)-1β, IL-1R1, caspase-3 mRNA levels decreased and the level of IL-1RN mRNA increased. Lung mechanics improved after BMDC therapy. The presence of male donor cells in lung tissue was not observed using detection of Y chromosome DNA. Conclusion: repeated administration of BMDCs reduced inflammation, fibrogenesis, and elastogenesis, thus improving lung mechanics through the release of paracrine factors.

Silicosis

10.1159/000356603

Cite

Citations (30)

Infusion of Bone Marrow Mononuclear Cells Reduces Lung Fibrosis but Not Inflammation in the Late Stages of Murine Silicosis

PLoS ONE (2014)

Miquéias Lopes‐Pacheco Túlio Galvão Ventura Helena Oliveira Leonardo Campos Monção-Ribeiro Bianca Gutfilen

We hypothesized that infusion of bone marrow mononuclear cells (BMMCs) in the late stages of silica-induced damage would reduce the remodelling process in a murine model of silicosis. C57BL/6 mice were assigned to 2 groups. In the SIL group, mice were instilled with a silica particle suspension intratracheally. Control (C) mice received saline under the same protocol. On the 40th day, some of the animals from both groups were killed. The others were treated with either saline or BMMCs (1×106cells) intravenously (C+BMMC and SIL+BMMC), and the mice were killed 70 days after the start of the protocol. In the mice in the SIL+BMMC group, collagen deposition, the presence of silica particles inside nodules, the presence of macrophages and cells reactive for inducible nitric oxide synthase were reduced. Lung parameters also improved. Beyond that, the total and differential cellularity of bronchoalveolar lavage fluid, immunoexpression of transforming growth factor-β, the number of T regulatory cells and apoptosis were increased. However, the presence of male donor cells in lung tissue was not observed using GFP+ cells (40d) or Y chromosome DNA (70d). Therefore, BMMC therapy in the late stages of experimental silicosis improved lung function by diminishing fibrosis but inflammatory cells persisted, which could be related to expansion of T regulatory cells, responsible for the beneficial effects of cell therapy.

Silicosis

10.1371/journal.pone.0109982

Cite

Citations (27)

Current understanding of the immunosuppressive properties of mesenchymal stromal cells

Journal of Molecular Medicine (2019)

Lígia Lins de Castro Miquéias Lopes‐Pacheco Daniel J. Weiss Fernanda F. Cruz Patrícia R. M. Rocco

10.1007/s00109-019-01776-y

Cite

Citations (103)

Rescuing ABCA4 trafficking mutants as a treatment for Stargardt disease.

Liudmila Cebotaru Miquéias Lopes‐Pacheco Inna Sabirzhanova Daniele Rapino Rahul Grover

ABCA4

Stargardt disease

Cite

Citations (0)

A real-life study of elexacaftor-tezacaftor-ivacaftor therapy in people with cystic fibrosis in Brazil

Pulmonology (2023)

L.Z. Salomão Rodrigo Abensur Athanazio Samia Zahi Rached Miquéias Lopes‐Pacheco Mariana Camargo

Ivacaftor

10.1016/j.pulmoe.2023.03.008

Cite

Citations (3)

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

Journal of Personalized Medicine (2022)

Iris A. L. Silva Onofrio Laselva Miquéias Lopes‐Pacheco

The development of preclinical in vitro models has provided significant progress to the studies of cystic fibrosis (CF), a frequently fatal monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Numerous cell lines were generated over the last 30 years and they have been instrumental not only in enhancing the understanding of CF pathological mechanisms but also in developing therapies targeting the underlying defects in CFTR mutations with further validation in patient-derived samples. Furthermore, recent advances toward precision medicine in CF have been made possible by optimizing protocols and establishing novel assays using human bronchial, nasal and rectal tissues, and by progressing from two-dimensional monocultures to more complex three-dimensional culture platforms. These models also enable to potentially predict clinical efficacy and responsiveness to CFTR modulator therapies at an individual level. In parallel, advanced systems, such as induced pluripotent stem cells and organ-on-a-chip, continue to be developed in order to more closely recapitulate human physiology for disease modeling and drug testing. In this review, we have highlighted novel and optimized cell models that are being used in CF research to develop novel CFTR-directed therapies (or alternative therapeutic interventions) and to expand the usage of existing modulator drugs to common and rare CF-causing mutations.

Personalized Medicine

Translational Medicine

Drug Development

10.3390/jpm12081321

Cite

Citations (21)

Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor

Molecules (2024)

Filipa C. Ferreira Camilla D. Buarque Miquéias Lopes‐Pacheco

The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators—small molecules acting on the basic molecular defect in CF—have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA’s) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.

Ivacaftor

Potentiator

Combination therapy

10.3390/molecules29040821

Cite

Citations (6)