STIMULATE · STING signalling modulation via the Electron Transport Chain
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-07-01 → 2023-06-30
- EU contribution
- €160,932
- Participants
- 1
- Scheme
- MSCA-IF
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Results in brief
STING signalling modulation via the Electron Transport Chain
This project, STIMULATE, was carried out in the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, under the supervision of Dr. David Sancho. STIMULATE began in an attempt to characterise the metabolic changes that occur in macrophages upon stimulation with different immune stimuli, in particular focusing on the Stimulator of Interferon Genes (STING)-dependent cytoplasmic DNA sensing pathway. STING is an adapter protein essential for the innate immune response to cytosolic double stranded DNA (dsDNA) and has been shown to be important in a wide range of clinical scenarios, in the context of viral and bacterial infection, cancer, and autoimmunity. Upon activation of STING, there is strong downstream activation of several inflammatory cytokines, including Type I interferons (IFN-I) and IFN stimulated genes important in the immune response against viruses and other pathogens. Despite the growing interest in immunometabolism and the potential for targeting these axes in human disease, the relationship between STING signalling and cellular metabolism is not known. Our objectives were to use a variety of techniques to study cellular metabolism in cells with or without STING stimulation. Then based on our findings, to try and find a link between the immune signalling pathway and the metabolic machinery focusing on mitochondrial targets. The mitochondria is the main metabolic hub in the cell, important not just for energy production but for the supply of building blocks required for cellular function and effective immune responses. To find these interaction partners our aim was to stimulate cells with STING agonists and perform proteomics of the mitochondria to determine interaction partners. Then, based on the direction of the data, we planned to use inhibitors and genetic approaches to characterise the effect of inhibiting upregulated metabolic pathways on STING signalling. Macrophages have various functions within the body both in homeostasis and inflammation. We aimed to investigate their cytokine production, particularly the IFN-I response, and their ability to perform phagocytosis, one of their key functions.
Data: CORDIS, © European Union
Project objective
The innate immune response to cytosolic dsDNA via the cGAS-STING pathway has been shown to be essential in the response to various viral, bacterial and parasitic infections, in autoimmunity and in cancer. However, the relationship between STING signalling and metabolism is currently unknown. In recent years, our understanding of immunometabolism has also increased – it is becoming clear that metabolic adaptations are fundamental for immune responses. Due to its role in this wide range of clinical pathologies, the mechanism of STING signalling has received a great deal of scientific interest and several STING-targeting compounds are now reaching clinical trial stages of development. It is therefore important to understand the effect of STING activation on mammalian cells, as well as how to manipulate this response to the greatest effect. The research proposed here focuses on the relationship between cellular metabolism and innate immune signalling via STING, using an unbiased proteomics approach as well as targeted immunometabolism approaches to find STING modulating metabolic pathways.Having completed my PhD studies in immunology, I am pursuing a postdoctoral project, in the lab of Dr. David Sancho at the CNIC, that utilises my expertise and allows me to expand my technical horizons and enhance my career development. As an expert in innate immune signalling I believe that combining my knowledge with the Sancho lab’s expertise in cellular immunobiology and metabolism will lead to a better understanding of our immune system. As well as the expertise of my host lab, I will also benefit from the collaboration of leaders in proteomics and mitochondrial biology. This Individual Fellowship would greatly benefit my current research objectives and my career as a whole by allowing me to explore my research interests in a supportive environment, where I will receive the training required for the next stage of my research career.
Original text from CORDIS.
Participants
- CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.) · MadridCoordinatorSpain
Links
Data: CORDIS, © European Union