HEИндивидуална стипендия2022–2024

ForgettingNAFLD · Unravelling the pathogenic cell-cell circuits underlying the tissue memory of non-alcoholic fatty liver disease

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

Период: 2022-10-01 → 2024-09-30
Финансиране от ЕС: 175 920 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Черният дроб при мастната болест (NAFLD) може да запази „памет“ за минали възпаления чрез промени в ДНК на клетките. Разбирането на този механизъм помага да се разбере до каква степен органите се възстановяват напълно след отслабване.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Unravelling the pathogenic cell-cell circuits underlying the tissue memory of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) refers to a spectrum of disease states in which the liver undergoes profound changes ranging from non-symptomatic simple steatosis (build-up of fat in the liver) to the more end stages of the disease including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). With the ongoing obesity epidemic, NAFLD has a global prevalence of 25% and approximately a fifth of those patients will progress to NASH. For these last disease stages there are currently no treatment options other than liver transplant. During early stages of NAFLD a change in lifestyle and weight loss can alleviate symptoms in patients. However, it remains unclear to what degree the liver can fully recover. Recent work pioneered the idea that tissue develops a ‘memory’ of previous inflammatory events. If so, patients recovered from NAFLD following weight loss might also carry such a memory in their liver with potentially long-lasting effects. This memory can be carried by individual long-lived cells in the form of changed to the DNA structure (so called epigenetic changes). In the liver the various structural cells (hepatocytes, stellate cells and endothelial cells) are closely interlinked with a specific population of immune cells, the macrophages. Macrophages are found in all tissues and perform unique functions that are essential to maintain homeostasis in their respective organ. In the liver a large population of long-lived macrophages exists referred to as Kupffer cells (KCs). As these various cells in the liver form a close-knit circuit a ‘memory ‘in one population has the capacity to alter the complete liver circuitry. During NAFLD all the cells in the liver are heavily affected and could potentially carry such a memory. Hence the overall objective of this project is to investigate to what degree the various cells in the liver carry a memory following recovery of NAFLD.

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

Цел на проекта

With the obesity epidemic, global prevalence of non-alcoholic fatty liver disease (NAFLD) is currently at 25% and rising. NAFLD results from accumulation of excessive fat in the liver and covers a spectrum of disease states from simple steatosis (fatty liver) to severe non-alcoholic steatohepatitis (NASH). NAFLD patients are also at increased risk of developing secondary pathologies, including infections and paracetamol-induced liver damage, although the mechanisms behind this remain unclear. As no pharmacological treatment of NAFLD exists to date, patients are typically instructed to lose weight as this can alleviate symptoms. However, with the recent proposal of tissue memory of inflammation, including NAFLD, it is unclear if weight loss alone is sufficient to restore liver homeostasis or if recovered NAFLD patients remain more susceptible to secondary inflammatory events. Recently, the host labs have identified key cell-cell circuits that control the functional specialization of liver resident macrophages in the steady-state and fatty liver. These findings led me to hypothesize that NAFLD could lead to tissue memory by disrupting the interactions between resident liver cells and establish aberrant cell-cell circuits that maintain a pathological state even after weight loss. Furthermore, I postulate that this NAFLD memory could facilitate the relapse into NAFLD but also modulate susceptibility to secondary insults. Indeed, my preliminary data indicates altered susceptibility to paracetamol overdose. Here, I propose to use single-cell RNA sequencing and epigenetics to investigate how cell-circuits in the liver are perturbed after NAFLD regression and identify the signals underlying these alterations. This project will further our understanding on how liver circuits are distorted in disease and could provide therapeutic avenues to ‘reset’ pathogenic liver circuits in patients currently suffering from NAFLD or those in the process of weight loss and recovery.

Оригинален текст от CORDIS (на английски).

Участници

VIB VZW · ZWIJNAARDE - GENTКоординаторБелгия