Meritxell Espino-Guarch’s research while affiliated with Sidra Medicine and other places

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Publications (9)


CRISPR-Cas9-engineered T1D models.
Applications of Genome-Editing Technologies for Type 1 Diabetes
  • Literature Review
  • Full-text available

December 2023

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77 Reads

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8 Citations

International Journal of Molecular Sciences

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Laura Herrero

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Meritxell Espino-Guarch

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by the immune system. Although conventional therapeutic modalities, such as insulin injection, remain a mainstay, recent years have witnessed the emergence of novel treatment approaches encompassing immunomodulatory therapies, such as stem cell and β-cell transplantation, along with revolutionary gene-editing techniques. Notably, recent research endeavors have enabled the reshaping of the T-cell repertoire, leading to the prevention of T1D development. Furthermore, CRISPR–Cas9 technology has demonstrated remarkable potential in targeting endogenous gene activation, ushering in a promising avenue for the precise guidance of mesenchymal stem cells (MSCs) toward differentiation into insulin-producing cells. This innovative approach holds substantial promise for the treatment of T1D. In this review, we focus on studies that have developed T1D models and treatments using gene-editing systems.

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of the Heritable Genetic and Non-Genetic Factors that Contribute to the Predisposition for Atopic Diseases. Factors can be divided into two major categories. (1) Genetic factors including genetically encoded features such as SNPs and HLA haplotype, along with alterable non-genetically encoded epigenetic features including DNA methylation and histone acetylation status. (2) Non-Genetic factors consisting of developmental, environmental, and maternal influences including the maternal microbiome is all transmitted during fetal and/or early neonatal development.
Mechanisms of Allergic Disease Development. (A) Representative image depicting the first stage of an allergic response driven by the recognition of environmental allergens as inflammatory mediators by pattern recognition receptors (PRR) present on the surface of dendritic cells (DC) and epithelial cells in barrier tissues. Epithelial cells produce defensive cytokines including TSLP, IL-25 and IL-33 that modulate activated DC and direct naïve T cells towards the TH2 phenotype. In the absence of inflammatory stimuli, naïve T cells may be activated in a tolerogenic manner and differentiate to become peripherally induced Treg cells (pTreg), which in concert with thymically produced T regs (nTreg), mediate the dampening of inflammatory responses. Activated TH2 cells produce IL-4 and mediate B cell class switching and production of IgE. Together with ILC2, Th2 cells additionally produce IL-5 and IL-13 that regulate the activation of the innate immune system and induces migration of eosinophils, mast cells and basophils to the sites of inflammation, where IgE bound to the FcERI receptors on mast cells and basophils recognizes the cognate allergen. This induces degranulation and release of further inflammatory mediators including histamine, leukotrienes, and heparin. (B) Analysis of protein-protein interactions of the 216 genes identified by GWAS from Han et al. (19) using the STRING database (48). Identification of several clusters of highly relevant pathways that overlay with the known functional pathways previously associated with asthma and allergic diseases, including the major cytokines signals associated with TH2 differentiation (IL-2, IL-4 and IL-13) along with the downstream mediators of differentiation—STAT6 and GATA3—and transcription factors associated with Treg differentiation—FOXP1 and SMAD—which are involved in the TGFβ signaling (blue). Additionally, the TRAF1 signaling nexus is identified, where TRAF1 has previously been identified as a key factor in allergic inflammation and the regulation of IL-4 production (red) (49). FcERI signaling and interactions between TCR and MHCII (HLA-DQA1) are identified (green) and multiple pairs of protein-protein interactions integral for development of allergic inflammation are also identified (pink)—notably IL-33-IL1RL1 (50) and BATF3-BACH2 (51). Data displayed is developed using Cytoscape v.3.9 (52).
Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles

May 2022

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113 Reads

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11 Citations

Asthma is ranked among the most common chronic conditions and has become a significant public health issue due to the recent and rapid increase in its prevalence. Investigations into the underlying genetic factors predict a heritable component for its incidence, estimated between 35% and 90% of causation. Despite the application of large-scale genome-wide association studies (GWAS) and admixture mapping approaches, the proportion of variants identified accounts for less than 15% of the observed heritability of the disease. The discrepancy between the predicted heritable component of disease and the proportion of heritability mapped to the currently identified susceptibility loci has been termed the ‘missing heritability problem.’ Here, we examine recent studies involving both the analysis of genetically encoded features that contribute to asthma and also the role of non-encoded heritable characteristics, including epigenetic, environmental, and developmental aspects of disease. The importance of vertical maternal microbiome transfer and the influence of maternal immune factors on fetal conditioning in the inheritance of disease are also discussed. In order to highlight the broad array of biological inputs that contribute to the sum of heritable risk factors associated with allergic disease incidence that, together, contribute to the induction of a pro-atopic state. Currently, there is a need to develop in-depth models of asthma risk factors to overcome the limitations encountered in the interpretation of GWAS results in isolation, which have resulted in the missing heritability problem. Hence, multiomics analyses need to be established considering genetic, epigenetic, and functional data to create a true systems biology-based approach for analyzing the regulatory pathways that underlie the inheritance of asthma and to develop accurate risk profiles for disease.


Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients

March 2022

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172 Reads

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1 Citation

International Journal of Molecular Sciences

Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prevalence of HHL, which negatively impacts the quality of life. Here, we functionally validated the pathogenicity of the c.178G>C, p.E60Q mutation in the MYO6 gene, which was detected previously in a Qatari HHL family, using cellular and animal models. In vitro analysis was conducted in HeLa cells transiently transfected with plasmids carrying MYO6WT or MYO6p.E60Q, and a zebrafish model was generated to characterize the in vivo phenotype. Cells transfected with MYO6WT showed higher expression of MYO6 in the plasma membrane and increased ATPase activity. Modeling the human MYO6 variants in zebrafish resulted in severe otic defects. At 72 h post-injection, MYO6p.E60Q embryos demonstrated alterations in the sizes of the saccule and utricle. Additionally, zebrafish with MYO6p.E60Q displayed super-coiled and bent hair bundles in otic hair cells when compared to control and MYO6WT embryos. In conclusion, our cellular and animal models add support to the in silico prediction that the p.E60Q missense variant is pathogenic and damaging to the protein. Since the c.178G>C MYO6 variant has a 0.5% allele frequency in the Qatari population, about 400 times higher than in other populations, it could contribute to explaining the high prevalence of hearing impairment in Qatar.



L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction

April 2019

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461 Reads

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68 Citations

L-amino acid transporters (LATs) play key roles in human physiology and are implicated in several human pathologies. LATs are asymmetric amino acid exchangers where the low apparent affinity cytoplasmic side controls the exchange of substrates with high apparent affinity on the extracellular side. Here, we report the crystal structures of an LAT, the bacterial alanine-serine-cysteine exchanger (BasC), in a non-occluded inward-facing conformation in both apo and substrate-bound states. We crystallized BasC in complex with a nanobody, which blocks the transporter from the intracellular side, thus unveiling the sidedness of the substrate interaction of BasC. Two conserved residues in human LATs, Tyr 236 and Lys 154, are located in equivalent positions to the Na1 and Na2 sites of sodium-dependent APC superfamily transporters. Functional studies and molecular dynamics (MD) calculations reveal that these residues are key for the asymmetric substrate interaction of BasC and in the homologous human transporter Asc-1.





Citations (5)


... These studies not only provide new insights for basic science but also lay the groundwork for developing potential diabetes treatment strategies. With the continuous development of CRISPR technology, it is expected to play an even greater role in gene therapy, disease model establishment, and biomedical research across multiple fields [3,4]. ...

Reference:

Research on the application of CRISPR technology in the treatment of type 1 diabetes (T1D)
Applications of Genome-Editing Technologies for Type 1 Diabetes

International Journal of Molecular Sciences

... In spite of the extended studies devoted to the identification of single variants of candidate genes, this approach appears to be inadequate as allergic diseases are multifactorial diseases in which the single gene effect might be only partial or marginal and might be different in different moments of a diseases' clinical development [11]. In addition, genome-wide studies do not produce clear results useful in the prediction of allergic risk and prevention [12]. Non-Mendelian forms of inheritance, gene-gene interactions, or analyses of functional pathways might be more informative [13]. ...

Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles

... MYO6 is a central player in the mechanotransduction processes of the inner ear, facilitating the conversion of mechanical stimuli, like sound vibrations, into electrical signals. It is indispensable for preserving the structural integrity and organization of stereocilia bundles, the hair-like projections critical for detecting mechanical stimuli (Mohiddin et al., 2004;Alkowari et al., 2022). Normal functional MYO6, expresses in the inner hair cell in the cochlea, is a prerequisite for the structural integrity and proper functioning of inner ear hair cells, including endocytosis, ion channel regulation, anchoring of stereocilia and vesicle movement (Self et al., 1999;Hertzano et al., 2008;Oonk et al., 2013) collectively safeguarding the integrity of stereocilia form and function. ...

Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients

International Journal of Molecular Sciences

... The diagnostic rate for syndromic cases was 100%, while the diagnostic rate for non-syndromic cases was only 30%. This is likely due to the fact that environmental factors, such as CMV, can be more difficult to etiologically diagnose in non-syndromic HL [36]. Our study also found that the SR for a genetic HL diagnosis in cases with a positive family history was higher compared to cases with a negative family history. ...

Genetics and Acquired Hearing Loss

... Amino acid transporters assist in transferring amino acids across the plasma membrane and ions are necessary for the operation of some transporters [5]. They also take part in tissue functions such as nutrition absorption and endogenous and exogenous compound metabolite excretion through the epithelia [6]. They can be moved by coupling ions (like Na, K, H, CI, or anions), facilitated transporters, active transporters, symporters, antiporters, uniporters, or coupling ions [7]. ...

L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction