Project acronym METARNAFLAMMATION
Project The RNA bridge between IRE-1 and PKR leading to metaflammation: discovery and intervention in atherosclerosis
Researcher (PI) Ebru Erbay
Host Institution (HI) BILKENT UNIVERSITESI VAKIF
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary A close functional and molecular integration between metabolic and immune systems is crucial for systemic homeostasis and its’ deregulation is causally linked to obesity and associated diseases including insulin resistance, diabetes and atherosclerosis and known as cardiometabolic syndrome (CMS). Metabolic overload initiates a chronic inflammatory and stress response known as metaflammation and promotes the complications of CMS. The precise molecular mechanisms linking metabolic stress to immune activation and stress responses, however, remain elusive.
Earlier studies demonstrated metabolic overload stresses the endoplasmic reticulum (ER) and activates the unfolded protein response (UPR). ER is a critical intracellular metabolic hub orchestrating protein, lipid and calcium metabolism. These vital functions of ER are maintained by a conserved, adaptive stress response or UPR that emanates from its membranes. ER stress has emerged as a central paradigm in the pathogenesis of CMS and its reduction prevents atherosclerosis and promotes insulin sensitivity. However, a clear understanding of how metabolic stress is sensed and communicated by the ER is fundamental in designing specific and targeted therapy to ER stress in CMS. This application will investigate the ER stress response that can sense excess lipids and couple to inflammatory and stress responses, and whether its unique operation under metabolic stress can be suitable for therapeutic exploitation in CMS. This proposal tackles the unique modes of operation of two important players in the ER stress response that are coupled by metabolic stress, inositol-requiring enzyme-1 (IRE-1) and double-stranded RNA-activated kinase (PKR), by taking advantage of chemical-genetics to specifically modify their activities. When completed the proposed studies will have shed light on a little explored but central question in the field of immunometabolism regarding how nutrients engage inflammatory and stress pathways.
Summary
A close functional and molecular integration between metabolic and immune systems is crucial for systemic homeostasis and its’ deregulation is causally linked to obesity and associated diseases including insulin resistance, diabetes and atherosclerosis and known as cardiometabolic syndrome (CMS). Metabolic overload initiates a chronic inflammatory and stress response known as metaflammation and promotes the complications of CMS. The precise molecular mechanisms linking metabolic stress to immune activation and stress responses, however, remain elusive.
Earlier studies demonstrated metabolic overload stresses the endoplasmic reticulum (ER) and activates the unfolded protein response (UPR). ER is a critical intracellular metabolic hub orchestrating protein, lipid and calcium metabolism. These vital functions of ER are maintained by a conserved, adaptive stress response or UPR that emanates from its membranes. ER stress has emerged as a central paradigm in the pathogenesis of CMS and its reduction prevents atherosclerosis and promotes insulin sensitivity. However, a clear understanding of how metabolic stress is sensed and communicated by the ER is fundamental in designing specific and targeted therapy to ER stress in CMS. This application will investigate the ER stress response that can sense excess lipids and couple to inflammatory and stress responses, and whether its unique operation under metabolic stress can be suitable for therapeutic exploitation in CMS. This proposal tackles the unique modes of operation of two important players in the ER stress response that are coupled by metabolic stress, inositol-requiring enzyme-1 (IRE-1) and double-stranded RNA-activated kinase (PKR), by taking advantage of chemical-genetics to specifically modify their activities. When completed the proposed studies will have shed light on a little explored but central question in the field of immunometabolism regarding how nutrients engage inflammatory and stress pathways.
Max ERC Funding
1 362 921 €
Duration
Start date: 2014-01-01, End date: 2018-06-30
Project acronym MIRBATWAT
Project Role of miRNAs in brown and white adipose tissue differentiation and function
Researcher (PI) Mirko Trajkovski
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary "Mammals have two types of fat: brown and white, with opposing functions. The white adipose tissue (WAT) is an important regulator of the whole body homeostasis that also serves to store energy in form of triglycerides (TGs). The main function of the brown adipose tissue (BAT) is to catabolize lipids in order to produce heat, a function that can be induced by cold exposure or diet. Disruption of the normal differentiation or development of the WAT causes ectopic lipid storage and severe pathology in both humans and experimental animals. Increased BAT development leads to increased energy expenditure without causing dysfunction in other tissues, and is associated with a lean and healthy phenotype, outlining the manipulation of the fat stores as an obvious therapeutic objective. With the proposed research we will identify miRNAs and other factors that regulate BAT and WAT differentiation and function. We will distinguish the miRNAs that specifically regulate brown or white adipogenesis and are expressed in the respective precursors, and establish them as signatures for either cell type. We will also identify the molecular mechanisms of action of the identified miRNAs in regulation of adipose tissue differentiation and metabolism. Using in vitro and in vivo systems, linage tracing studies, transgenic animals, as well as cohorts of human patients, we will determine the origin of the beige cells within the SAT, establish their importance in the regulation of metabolism in vivo, and develop novel strategies to induce the brown fat differentiation and function. Finally, we will discover ways to exclusively silence miRNAs in the brown fat will that will allow us not only to investigate the miRNAs function specifically in the brown fat, but also to develop new strategies for treatment of dyslipedaemia, diabetes and obesity."
Summary
"Mammals have two types of fat: brown and white, with opposing functions. The white adipose tissue (WAT) is an important regulator of the whole body homeostasis that also serves to store energy in form of triglycerides (TGs). The main function of the brown adipose tissue (BAT) is to catabolize lipids in order to produce heat, a function that can be induced by cold exposure or diet. Disruption of the normal differentiation or development of the WAT causes ectopic lipid storage and severe pathology in both humans and experimental animals. Increased BAT development leads to increased energy expenditure without causing dysfunction in other tissues, and is associated with a lean and healthy phenotype, outlining the manipulation of the fat stores as an obvious therapeutic objective. With the proposed research we will identify miRNAs and other factors that regulate BAT and WAT differentiation and function. We will distinguish the miRNAs that specifically regulate brown or white adipogenesis and are expressed in the respective precursors, and establish them as signatures for either cell type. We will also identify the molecular mechanisms of action of the identified miRNAs in regulation of adipose tissue differentiation and metabolism. Using in vitro and in vivo systems, linage tracing studies, transgenic animals, as well as cohorts of human patients, we will determine the origin of the beige cells within the SAT, establish their importance in the regulation of metabolism in vivo, and develop novel strategies to induce the brown fat differentiation and function. Finally, we will discover ways to exclusively silence miRNAs in the brown fat will that will allow us not only to investigate the miRNAs function specifically in the brown fat, but also to develop new strategies for treatment of dyslipedaemia, diabetes and obesity."
Max ERC Funding
1 400 014 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym zebraHeart
Project Novel insights into cardiac regeneration through studies in the zebrafish
Researcher (PI) Nadia Isabel Mercader Huber
Host Institution (HI) UNIVERSITAET BERN
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary Myocardial infarction (MI) leads to cardiomyocyte death and accumulation of myofibroblasts (MFs) at the site of injury, which produce large amounts of extracellular matrix (ECM), generating a scar. Initially, cardiac fibrosis protects from ventricular wall rupture, but subsequent myocardial remodelling causes heart failure, representing a leading cause of death in Europe. While MFs play a central role in cardiac fibrosis, there is confusion on their origin, a lack of specific markers and the existence of a unique MF type is debatable. Different MF might reveal distinct characteristics regarding ECM production, contractility, and autophagy, making them more or less pernicious. While in humans cardiac fibrosis is irreversible, other vertebrates have a remarkable capacity to regenerate damaged tissue. We recently established a zebrafish MI model and found that cardiac fibrosis is reversible and occurs as an intermediate step during regeneration. Here, the endogenous mechanisms of MFs and ECM regression will be explored. In addition, MF origin, types and fate will be characterized and manipulated to improve regeneration. As in mammals, cardiac injury elicits an inflammatory response in the zebrafish. The regenerative capacity of a species has been directly linked to features of its immune system, but surprisingly little is known on zebrafish leukocyte subtypes. We will study the role of macrophages and particularly analyse a subtype, which accumulates in the outer mesothelial layer of the heart, the epicardium. Epicardial derived cells play a key role as a trophic factor and progenitor cell source, and a first step towards regeneration includes the reestablishment of the epicardial layer. The zebrafish will offer a screening platform for small molecules triggering its activation. In sum, the project will increase the knowledge on the molecular and cellular basis of fibrosis regression, provide novel MF markers and identify new drugs to enhance cardiac regeneration.
Summary
Myocardial infarction (MI) leads to cardiomyocyte death and accumulation of myofibroblasts (MFs) at the site of injury, which produce large amounts of extracellular matrix (ECM), generating a scar. Initially, cardiac fibrosis protects from ventricular wall rupture, but subsequent myocardial remodelling causes heart failure, representing a leading cause of death in Europe. While MFs play a central role in cardiac fibrosis, there is confusion on their origin, a lack of specific markers and the existence of a unique MF type is debatable. Different MF might reveal distinct characteristics regarding ECM production, contractility, and autophagy, making them more or less pernicious. While in humans cardiac fibrosis is irreversible, other vertebrates have a remarkable capacity to regenerate damaged tissue. We recently established a zebrafish MI model and found that cardiac fibrosis is reversible and occurs as an intermediate step during regeneration. Here, the endogenous mechanisms of MFs and ECM regression will be explored. In addition, MF origin, types and fate will be characterized and manipulated to improve regeneration. As in mammals, cardiac injury elicits an inflammatory response in the zebrafish. The regenerative capacity of a species has been directly linked to features of its immune system, but surprisingly little is known on zebrafish leukocyte subtypes. We will study the role of macrophages and particularly analyse a subtype, which accumulates in the outer mesothelial layer of the heart, the epicardium. Epicardial derived cells play a key role as a trophic factor and progenitor cell source, and a first step towards regeneration includes the reestablishment of the epicardial layer. The zebrafish will offer a screening platform for small molecules triggering its activation. In sum, the project will increase the knowledge on the molecular and cellular basis of fibrosis regression, provide novel MF markers and identify new drugs to enhance cardiac regeneration.
Max ERC Funding
1 499 215 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
