HEИндивидуална стипендия2023–2026

QuantiCl · Deconstructing the role of trans-cellular ion transport in organ formation and function

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2023-10-01 → 2026-03-31
Финансиране от ЕС: 189 687 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Транспортът на хлоридни йони през епителните клетки, например в панкреасните канали, се анализира чрез количествена биохимия и микроскопия. Разбирането на тези процеси помага да се установи как промени в отделните протеини водят до нарушаване на функциите на органите и развитие на болести.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Deconstructing the role of trans-cellular ion transport in organ formation and function

Many organs have of a complex structure with lumina and ducts, for example, the pancreas, liver, intestine, etc. Such organs rely on the transport of nutrients and other chemicals from the lumens to the tissue or vice versa for their function and development. These lumens and ducts are lined with epithelial cells, a polarized cell type that faces the lumen on one side (apical side) and the tissue on the other (basolateral side). The transport of nutrients is carried out by transport proteins embedded in both the basolateral membrane and the apical membrane. The interplay of individual transport proteins in transport processes cells is what ultimately leads to the net transport events, but a solid molecular understanding of these biochemical processes is lacking. Solute transport across epithelia is a molecular process, but leading edge studies until now mainly revolve around bulk measurements, where all transporters are considered but not their unique interplay. This implies that mathematical models based on such measurements have limited predictive value when it comes to the single transport proteins. Changes in single proteins can however easily lead to disruptions in function and to diseases. QuantiCl aims to bridge this knowledge gap by studying transcellular transport using quantitative biochemistry in epithelial cells and organoids, with specifically Chloride as the target. Chloride is an important anion in the function of many organds, for example, it is exchanged for bicabonate throughout the pancreatic duct, which is then used to neutralize stomach acid, but it is also believed to play a role in lumen formation. Using a combination of fluorescent chloride sensors in organoids, microscopy and an image and analysis pipeline QuantiCl aims to provide quantitative insights into transcellular chloride transport, within the full complexity of the native cellular environment. These insights will provide key fundamental knowledge on how (membrane) proteins work together and take part in forming complex biological systems.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Solute transport across epithelial cells is of vital importance for the function and development of many organs, for instance, the pancreas, liver, and intestine. Within the pancreas, bicarbonate is secreted from the ducts in order to neutralize stomach acid in the duodenum. The secretion of bicarbonate over the epithelial membrane is coupled to chloride transport in the opposite direction. The mechanism of this transport is complex due to the redundancy of transporters, protein-protein interactions, and multiple regulation and signaling mechanisms. Thus far the field relies on either bulk measurements, for example using Ussing chambers, or studies on isolated individual proteins. A more profound and quantitative understanding of epithelial transport cannot be obtained solely by either of these strategies but requires a combination of both: addressing individual proteins within their native cellular environment. Therefore, I will establish the contribution of individual transporters in epithelial chloride transport in human pancreatic duct cells by using inhibiting nanobodies to perturb the system. Then I will determine the plasticity and response of the cells to these inhibitions by measuring protein expression using transcriptomics and quantitative mass-spectrometry. Next, I will perform quantitative chloride measurements across epithelial cells, simulating in-organ conditions by changing the composition of the apical solution. Finally, I will elucidate the role of chloride transport in pancreatic duct formation by inhibiting key chloride transporters in 3D pancreatic organoids. Taken together this project will yield quantitative insights into transcellular chloride transport, within the full complexity of the native cellular environment.

Оригинален текст от CORDIS (на английски).

Участници

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENКоординаторГермания