Projektbeschreibung
Kalzium-Regulierung der Schleimstoffsekretion
Das Epithel der Atemwege und des Magen-Darm-Trakts ist von einer Schleimschicht bedeckt, die von Becherzellen produziert wird. Diese können ihre Sekretionseigenschaften modifizieren, um sich an die kontinuierlichen Veränderungen im Epithel anzupassen. Die am häufigsten vorkommenden Proteine in der Schleimschicht sind Mucine. Defekte in der Schleimsekretion verursachen Schleimanomalien, epithelialen Stress und Funktionsstörungen, die zu mikrobiellen Infektionen, chronischen Entzündungen und aggressiveren Krankheitsbildern wie etwa zystischer Fibrose, Asthma und chronisch obstruktiver Lungenerkrankung führen können. Das EU-finanzierte Projekt ICaRMuSs wird erkunden, wie Kalzium den Transport, die Sortierung und die Sekretion von Mucinen reguliert, neue Erkenntnisse über die Schleimphysiologie liefern und ermitteln, welche Membranproteine für die Schleimsekretion wichtig sind.
Ziel
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.
Wissenschaftliches Gebiet
- medical and health sciencesclinical medicinepneumologyasthma
- natural scienceschemical sciencesinorganic chemistryalkaline earth metals
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepathology
- medical and health sciencesbasic medicinephysiology
Programm/Programme
Thema/Themen
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
MSCA-IF-EF-ST - Standard EFKoordinator
08003 Barcelona
Spanien