H2020Индивидуална стипендия2019–2021

VOLIV · Role of volume-regulated anion channels in liver physiology and metabolism

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2019-08-01 → 2021-07-31
Финансиране от ЕС: 159 461 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Специални канали (VRAC) регулират обема на клетките в черния дроб, което влияе върху метаболизма на мазнините и въглехидратите. Разбирането на този процес може да помогне при търсенето на методи за лечение на метаболитни заболявания като неалкохолен стеатохепатит.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Role of volume-regulated anion channels in liver physiology and metabolism

The volume of animal cells needs to be tightly controlled, especially upon osmotic challenges but also during cell growth, migration and death. Cellular volume changes are also believed to have a role in cell signaling, in particular for insulin secretion by pancreatic β-cells and liver metabolism. Indeed, several studies established that anabolic processes (e.g. induced by insulin) are associated with swelling and catabolic processes (e.g. induced by glucagon) with shrinkage of hepatocytes, the main epithelial cells in the liver. However, the causal relationship between changes in hepatocyte volume and liver metabolism is largely obscure. Under physiological conditions, postprandial uptake of nutrients such as amino acids would increase hepatic metabolism after induction of osmotic cell swelling. The question of how hepatocyte swelling is sensed and transduced to regulate metabolism also remains unanswered. As major player in cell volume regulation, the Volume-Regulated Anion Channel VRAC may influence liver metabolism by controlling hepatocyte volume. In parallel with another group, VRAC has been identified by the host laboratory as LRRC8 heteromers with LRRC8A being the obligatory subunit. With the recent identification of LRRC8 subunits as VRAC components, it is now possible to rigorously assess physiological roles of VRAC in the liver and its metabolic pathways. Because the liver is a key organ controlling lipid and carbohydrate metabolism, dysregulations of hepatic signaling pathways can lead to metabolic diseases. If some cascades are identified as regulated by VRAC, this channel may therefore represent an interesting therapeutic target for the treatment of metabolic diseases such as the non-alcoholic steatosis hepatitis (NASH). The overarching aim of this study was thus to (i) investigate the role of VRAC in liver function and in particular, (ii) to determine whether it is involved in the coupling of cell swelling with metabolism in hepatocytes.

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

Цел на проекта

A fundamental property of animal cells is the ability to maintain their volume constant to face changes in osmolarity and during division, migration and transepithelial transport. There is emerging evidence that cell swelling also initiates signaling cascades that regulate metabolism, particularly in hepatocytes. However, the basic mechanisms responsible for sensing volume changes and initiating volume-regulated signaling cascades in the liver remain largely unclear. As major player in cell volume regulation, the Volume-Regulated Anion Channel VRAC may influence liver metabolism by controlling hepatocyte volume. VRAC was recently identified by the host laboratory as LRRC8 heteromers. LRRC8A represents the obligatory subunit and forms heteromers with LRRC8B-E isoforms. Depending on the subunit composition, the heteromers present specific electrophysiological properties and transport different substrates.The aim of this proposal is then (i) to investigate the role of VRAC and its different subunits in liver function and particularly (ii) as signal transducer between hepatocyte volume and metabolism.The host laboratory already generated numerous LRRC8 mouse models e.g. tagged-Lrrc8 knock-in mice which are valuable tools to determine the subcellular distribution of the different LRRC8 subunits in the liver. I will also develop hepatocyte-specific knock-out (KO) mice to analyze the liver histology and function. Primary hepatocytes from the different KO will be used to study the potential roles of VRAC in liver physiology at the cellular level e.g. via autocrine signaling cascades. I finally intend to identify the VRAC-dependent hepatic metabolic pathways using large-scale analytical techniques and evaluate the systemic metabolism of the different KO mice. My project is expected to uncover the role of VRAC in liver physiology from molecular to systemic level and thus to provide detailed insights of the molecular coupling between hepatocyte volume and liver metabolism.

Оригинален текст от CORDIS (на английски).

Участници

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC) · BerlinКоординаторГермания