Periodic Reporting for period 1 - EndoConnect (EU Training Network in understanding the molecular regulation and the role of endo-lysosomal processes in cardio-metabolic diseases)
Période du rapport: 2021-01-01 au 2022-12-31
Cardio-metabolic diseases, such as cardiovascular disease, type-2 diabetes and non-alcoholic fatty liver disease, are becoming a serious health problem worldwide. To improve healthcare, we need to increase our understanding of how these diseases develop.
In the EndoConnect consortium, we focus on a specific system in the cell, named the endo-lysosomal system, that allows the cell to communicate with its environment and to adapt to changes that occur both outside as well as inside the cell. As a result, this system helps to keep cells, organs and, subsequently, our body healthy. In our consortium, we bring scientists from different European countries and research fields together to study this system at a cellular and organismal level, with the aim to ultimately improve medical care.
At the same time, the EndoConnect consortium provides young scientists (PhD students) an international training program to help them successfully kick off their career. Through this training program, the young scientists, also referred to as early-stage researchers (ESRs), will not only train their competencies on a scientific and technical level, but they will also develop their transferable skills to enhance their career options – whether it will be inside or outside academia.
We expect that the EndoConnect consortium will increase our understanding of how cardio-metabolic diseases develop, and that the basic knowledge generated about the endo-lysosomal system will help us to pave the road for novel diagnostics and therapeutics. While doing this, the EndoConnect consortium contributes to train the next generation of interdisciplinary scientists that will innovate and shape the future of basic and medical science.
In the EndoConnect consortium, we focus on a specific system in the cell, named the endo-lysosomal system, that allows the cell to communicate with its environment and to adapt to changes that occur both outside as well as inside the cell. As a result, this system helps to keep cells, organs and, subsequently, our body healthy. In our consortium, we bring scientists from different European countries and research fields together to study this system at a cellular and organismal level, with the aim to ultimately improve medical care.
At the same time, the EndoConnect consortium provides young scientists (PhD students) an international training program to help them successfully kick off their career. Through this training program, the young scientists, also referred to as early-stage researchers (ESRs), will not only train their competencies on a scientific and technical level, but they will also develop their transferable skills to enhance their career options – whether it will be inside or outside academia.
We expect that the EndoConnect consortium will increase our understanding of how cardio-metabolic diseases develop, and that the basic knowledge generated about the endo-lysosomal system will help us to pave the road for novel diagnostics and therapeutics. While doing this, the EndoConnect consortium contributes to train the next generation of interdisciplinary scientists that will innovate and shape the future of basic and medical science.
To achieve the EndoConnect goals, different model systems are needed, including cellular and experimental mouse models. In the first reporting period of the EndoConnect consortium, many of the ESRs successfully generated these model systems. In fact, in one of the EndoConnect projects, the ESRs improved the methodology by which these specific models are generated. At this moment, most of the model systems are in place and are being characterized in depth.
In one of the models, we identified a new factor in the metabolism of cholesterol. Cholesterol is a specific type of lipid, and high blood cholesterol levels increase the risk of cardiovascular disease. Currently, the mechanism by which this new factor regulates cholesterol levels is being investigated in collaboration with several partners of EndoConnect.
The liver removes cholesterol from our bloodstream using a specific molecule, named the low-density lipoprotein receptor (LDLR). LDLR can be broken down within liver cells using a specific degradation machinery. Hence, when LDLR is broken down, the levels of cholesterol in the blood rise. In one of the EndoConnect projects, a combination of techniques is used to identify the factors that bring LDLR to the degradation machinery within the liver cells. A large list of potential factors has been identified and will be further studied in detail.
A change in diet can affect the organization of the endo-lysosomal system, and thereby allow cells and organs to adapt to this so-called metabolic challenge. To identify the key players of the endo-lysosomal system that are changed by metabolic challenges, the ESRs have established a specific cellular model system in which they can mimic these challenges. This new cell culture system is currently being used by several ESRs.
In addition, several other novel factors that play a role in the endo-lysosomal system have been identified using an array of different approaches. The role of these new factors in lipid and glucose metabolism is currently being investigated in both cellular and experimental mouse models. In mice, we are focussing on specific organs such as the liver, adipose tissue, and the intestine: in other words, all metabolically active organs.
Furthermore, partners of the EndoConnect consortium showed that some factors form a large complex and thereby act together to regulate the endo-lysosomal system. Using sophisticated technologies, including high resolution microscopy and biochemical assays, we provided a picture of how these factors act together, where they are localized in the cell, and how they control the cell’s communication with its environment.
Meanwhile, several training events were organized for the ESRs in the first reporting period of the EndoConnect consortium. These included scientific lectures about specific cellular and metabolic pathways and techniques, but also a training program to show the ESRs how to use a big data platform for their research. Several ESRs have used (or are still using) this program and follow up studies are being conducted. Furthermore, the ESRs were introduced to a personal coach that helped them to identify their strengths and weaknesses and learn how to train and improve their personal skills. Particular attention was also paid to data management, the generation of FAIR data and open science, ethics concerning scientific integrity, diversity (Women in Science), and communication skills. Finally, the ESRs were trained how to design scientific posters, how to present a poster and how to strongly pitch their research projects. All these skills are important assets that will help them to pursue successful scientific careers.
In one of the models, we identified a new factor in the metabolism of cholesterol. Cholesterol is a specific type of lipid, and high blood cholesterol levels increase the risk of cardiovascular disease. Currently, the mechanism by which this new factor regulates cholesterol levels is being investigated in collaboration with several partners of EndoConnect.
The liver removes cholesterol from our bloodstream using a specific molecule, named the low-density lipoprotein receptor (LDLR). LDLR can be broken down within liver cells using a specific degradation machinery. Hence, when LDLR is broken down, the levels of cholesterol in the blood rise. In one of the EndoConnect projects, a combination of techniques is used to identify the factors that bring LDLR to the degradation machinery within the liver cells. A large list of potential factors has been identified and will be further studied in detail.
A change in diet can affect the organization of the endo-lysosomal system, and thereby allow cells and organs to adapt to this so-called metabolic challenge. To identify the key players of the endo-lysosomal system that are changed by metabolic challenges, the ESRs have established a specific cellular model system in which they can mimic these challenges. This new cell culture system is currently being used by several ESRs.
In addition, several other novel factors that play a role in the endo-lysosomal system have been identified using an array of different approaches. The role of these new factors in lipid and glucose metabolism is currently being investigated in both cellular and experimental mouse models. In mice, we are focussing on specific organs such as the liver, adipose tissue, and the intestine: in other words, all metabolically active organs.
Furthermore, partners of the EndoConnect consortium showed that some factors form a large complex and thereby act together to regulate the endo-lysosomal system. Using sophisticated technologies, including high resolution microscopy and biochemical assays, we provided a picture of how these factors act together, where they are localized in the cell, and how they control the cell’s communication with its environment.
Meanwhile, several training events were organized for the ESRs in the first reporting period of the EndoConnect consortium. These included scientific lectures about specific cellular and metabolic pathways and techniques, but also a training program to show the ESRs how to use a big data platform for their research. Several ESRs have used (or are still using) this program and follow up studies are being conducted. Furthermore, the ESRs were introduced to a personal coach that helped them to identify their strengths and weaknesses and learn how to train and improve their personal skills. Particular attention was also paid to data management, the generation of FAIR data and open science, ethics concerning scientific integrity, diversity (Women in Science), and communication skills. Finally, the ESRs were trained how to design scientific posters, how to present a poster and how to strongly pitch their research projects. All these skills are important assets that will help them to pursue successful scientific careers.
At this moment, many different model systems are being characterized and novel factors are being studied to understand their roles in regulating the endo-lysosomal system and their contribution to the development of cardio-metabolic diseases. We expect that we will identify novel pathways that explain why certain individuals suffer from high blood and liver cholesterol levels and are at risk to develop cardiovascular disease and fatty liver disease. Furthermore, the identified pathways can be useful to find novel therapeutic targets to lower plasma cholesterol, treat fatty liver disease and type 2 diabetes.
Although the EndoConnect projects have a strong fundamental character, we believe that by improving our knowledge on how cellular processes are regulated, we can develop specific therapeutic strategies to treat cardiometabolic diseases in the future. With our industrial partners we have direct access to knowledge and expertise how to develop these therapies.
Furthermore, the EndoConnect training programs will educate the next generation of interdisciplinary scientists that will shape the future of basic and medical science.
Although the EndoConnect projects have a strong fundamental character, we believe that by improving our knowledge on how cellular processes are regulated, we can develop specific therapeutic strategies to treat cardiometabolic diseases in the future. With our industrial partners we have direct access to knowledge and expertise how to develop these therapies.
Furthermore, the EndoConnect training programs will educate the next generation of interdisciplinary scientists that will shape the future of basic and medical science.