Descripción del proyecto
Cómo regula el calcio la secreción de la mucina
El epitelio de las vías respiratorias y el tracto gastrointestinal está cubierto por una capa mucosa producida por las células caliciformes, que pueden modificar sus propiedades secretoras para adaptarse a los cambios continuos en el epitelio. Las proteínas más abundantes en la capa mucosa son las mucinas. Los defectos en la secreción de las mucinas causan anomalías mucosas, estrés epitelial y disfunciones que pueden dar lugar a infecciones microbianas, inflamación crónica y patologías más agresivas como la fibrosis quística, el asma y la enfermedad pulmonar obstructiva crónica. El proyecto ICaRMuSs, financiado con fondos europeos, abordará cómo regula el calcio el transporte, la clasificación y la secreción de mucinas, proporcionará nuevos datos sobre la fisiología del moco y determinará qué proteínas de membrana son importantes para la secreción de la mucina.
Objetivo
The epithelium in the airways and gastrointestinal track are covered by a mucus layer which protects the epithelium from mechanical and microbial insults. The most abundant proteins in the mucus layer are mucins which are synthesized and secreted by goblet cells. Mucus function is largely dictated by mucin composition and goblet cells can modify their secretory properties to adapt to the continuous changes the epithelium is encountered with. Mucins are heavily glysosylated and packed into secretory vesicles in the Golgi apparatus. A calcium signal triggers the fusion of the secretory vesicles with the plasma membrane releasing mucins to the extracellular space. The role of intragranular calcium remains a mayor gap in our understanding of mucin physiology and how goblet cells precisely control mucus composition remains only a matter of speculation. These are highly relevant questions as defects in mucin secretion cause mucus abnormalities, epithelial stress and dysfunction that can lead to microbial deleterious infections, chronic inflammation and more aggressive pathologies such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease.
In this project I will address how calcium regulates the trafficking, sorting and secretion of mucins, filling current gaps in our understanding of mucus physiology. I will genetically engineer mucin-secreting cells with the CRISPR/Cas9 tools to add GFP and RFP to MUC5AC and MUC2 loci and describe granular composition by super resolution microscopy and FACS. I will use a first-in its kind probe to measure intragranular calcium concentration and finally I will purify secretory granules and sequence them with mass spectrometry to determine which membrane proteins are important for mucin secretion. This project will allow me to apply my experience in highly relevant questions in cell biology and it will also enhance my creative and innovative potential through advanced training and international mobility.
Ámbito científico
- medical and health sciencesclinical medicinepneumologyasthma
- natural scienceschemical sciencesinorganic chemistryalkaline earth metals
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepathology
- medical and health sciencesbasic medicinephysiology
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
08003 Barcelona
España