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Myriam Aouadi group

Research focus

Since the discovery of macrophages in adipose tissue, many laboratories have focused their effort on understanding the contribution of these immune cells to metabolic diseases. Despite great progress in characterizing obesity as a state of low-grade inflammation, very little is known about the multiple phenotypes and functions of macrophages in metabolic tissues. The lack of methods to carefully investigate cell-to-cell variability in macrophage phenotype and to manipulate gene expression in a cell-specific manner has delayed answering these crucial questions. Our lab takes advantage of sophisticated methods to investigate macrophage subpopulations and their function in obesity-associated metabolic complications.

Projects

Study the mechanism whereby factors produced by liver macrophages regulate insulin sensitivity.

We have recently discovered that mice fed a high fat diet (HFD) become rapidly obese and insulin resistant independently of liver inflammation, which was thought to be an important driver in obesity-induced insulin resistance. On the other hand, depletion studies have shown that removing liver macrophages (LMs) prevents insulin resistance induced by obesity, suggesting an important role of LMs in the regulation of insulin sensitivity. Using RNAseq, we identified genes specifically expressed by liver macrophages, whose expression significantly increases with obesity and insulin resistance. We then took advantage of a powerful and unique tool, called glucan encapsulated RNAi particles (GeRP), that deliver siRNA and silence genes specifically in macrophages in vivo.

This technology is based on small interfering RNA (siRNA) encapsulated within glucan particles derived from baker’s yeast. By using intraperitoneal injections, we showed that GeRPs delivered siRNA and silenced genes specifically in macrophages in the adipose tissue of obese mice. However, by using intravenous administration, we showed that GeRPs delivered siRNA and silenced genes in LMs but not in hepatocytes or macrophages within other tissues.

Using this unique method, we found that silencing genes of interest specifically in LMs improves insulin sensitivity in obese mice. This project has so far confirmed that liver macrophages can play a role in the regulation of insulin sensitivity independantly of inflammation. This opened a new avenue towards the discovery of the multiple roles of immune cells other than only the inflammatory response.

Identify distinct phenotypes and functions of macrophages in liver and adipose tissue.

Macrophages are able to modulate their properties upon contact with different cell types as well as extracellular matrix. Their intrinsic heterogeneity during differentiation is compounded by reciprocal interactions with neighbouring cells, including other macrophages. In many different tissues, macrophages can occupy different anatomical niches and perform specialized functions even within the same organ. Emerging data suggest that macrophages acquire specialized functions, which are tailored for assisting local homeostasis, within each particular organ.

We use scRNAseq, metabolomics, flow cytometry, CytOF and in situ transcriptomic to study the heterogeneity of resident macrophage in liver and adipose tissue in health and metabolic disease.

Decoding the phenotype of macrophages through the study of non-coding RNA

We aim at identifying dysregulated genes but also non-coding RNAs such as microRNAs, enhancer RNAs, and long non-coding RNAs which have recently emerged as important regulators of gene expression, and which expression have been associated with several diseases.

Using the Global Run-On sequencing (GRO-seq) to directly measure rates of nascent transcription genome-wide, we propose to identify all transcript, genes and non-coding RNAs dysregulated in LMs in obesity that could be involved in the development of insulin resistance.

We are especially interested in enhancers, which are regions of DNA important for the regulation of genes transcription, and can be transcribed as non-coding RNAs called enhancer-derived RNAs (eRNAs).

The eRNAs can regulate the expression of the nearby gene, and have also been shown to be superior markers for active enhancers because of their small size and high dynamic ranges.

The mining of the GRO-seq data for eRNAs transcription to map functional enhancers, combined with genome-wide de novo motif analysis performed at sites of eRNAs dysregulation in LMs from obese and insulin resistant mice compared to lean mice, will allow us to identify the transcription factor(s) that could be involved in gene dysregulation in LMs in obesity.

Funding

  • Integrated Cardio Metabolic Center/Astrazeneca start-up fund (2015-2020).
  • Swedish Research Council (2016-2020).
  • Roft Luft foundation through the SRP Diabetes at Karolinska Institutet (2016-2017).
  • Novonordisk Foundation through the Tripartite Immuno-metabolism Consortium (2016-2020).
  • Diabetes Wellness Foundation (2017)

Members

Myriam Aouadi research group

Myriam Aouadi, PhD, Group leader

I received my PhD in June 2006 from the University of Nice Sophia-Antipolis, France, in the laboratory of Yannick Le Marchand-Brustel. My worked focussed on the role of MAPK pathways in the commitment of embryonic stem cells in different lineages. I found that p38MAPK is an important player in the early steps of neurogenesis and myogenesis, while it is required for the late stages of adipogenesis. In 2006, I joined the laboratory of Michael Czech at the University of Massachusetts to work on the emerging field of immunometabolism, that investigates the interactions between immune and metabolic cells. During my postdoctoral studies, I developed a method to deliver siRNA specifically to macrophages in vivo. This unique technology allows the study of particular factors expressed by macrophages specifically. In 2009, I became assistant professor at the University of Massachusetts and used this novel technology to show that while macrophages in the adipose tissue could be detrimental to insulin sensitivity they could be beneficial as well.

I started my laboratory at the Integrated Cardio-Metabolic Center at the Karolinska institute in 2015. My lab investigates the multiple roles and heterogeneity of liver and adipose tissue macrophages in metabolic diseases.

Team work, curiosity, passion and enthusiasm are the important qualities that I am looking for and found in my lab members.

Emelie Barreby, PhD student

After obtaining my Master’s degree in Biomedicine at Karolinska Institutet I joined the lab of Myriam Aouadi in 2015, working as a research technician. My interest was to gain experience from working in a lab using state of the art techniques such as RNA-sequencing and targeted gene silencing. During this experience, inspired by Myriam and her research group, I decided to pursue a PhD and register for the doctoral program in 2017. Today, my work involves investigating the phenotype of liver macrophages to better understand their role during the pathogenesis of metabolic diseases by using techniques such as flow cytometry, CyTOF and single cell RNA sequencing.

As part of my doctoral training I also have the benefit of working side-by-side with bioinformaticians in the center to get trained in bioinformatics. In this way, I have had the opportunity to gain knowledge of the whole process from isolating cells and preparing RNA sequencing libraries to actually analyzing the sequencing data myself.

Cecilia Morgantini, MD, PhD, Postdoctoral fellow

Since the beginning of my medical training I had the desire to help people and the passion to understand the causes of their diseases. After a PhD in clinical physiology, driven by the idea to understand more about the molecular mechanism behind metabolic disorders, I joined the laboratory of Dr. Aouadi in 2015. In Aouadi’s lab using unique and sophisticated techniques allowing analysis and manipulation of gene expression at cellular level, I am studying the interaction between immune and metabolic cells. I strongly believe that combining basic research with clinical practice will improve the quality of patients’ care and will help to identify new customized treatments.

Laura Levi, Lab manager, PhD

I obtained my masters in industrial biotechnology at the University Federico II of Naples. For two years, I worked as a technician at the research center of Novartis Vaccines & Diagnostics in Siena. Next I enrolled in graduate school at Karolinska Institutet; my PhD focused on the connection between chronic infection and cancer development in vitro and in vivo. I joined Dr. Aouadi’s lab in January 2016 and since then I had the opportunity to work in a very dynamic and enthusiastic group. We are always developing unique and novel strategies to understand metabolic diseases. Our goal is to contribute to improving the patients’ quality of life.

As a lab manager, I provide technical and scientific support in all the different projects.

André Sulen, Postdo, PhD

I graduated as a PhD from the University of Bergen in 2016. My project evaluated signal transduction in blood leukocytes as biomarkers for environmental stress exerted on the healthy population. It is well known that environmental cues regulate metabolism by modulating monocyte and macrophage transcriptional programs. In Myriam Aouadi´s group we use cutting-edge single-cell technologies, such as single-cell RNAseq and CyTOF, to better characterize the role of immune cells in metabolic tissues during obesity and development of type 2 diabetes. More specifically, my project aims to characterize macrophages in adipose tissue. Our objective is to increase our understanding of metabolic disease by using unbiased approaches that allow the discovery of new biological concepts and eventually novel therapeutic strategies to tackle diabetes.

Connie Xu (M.Sc. in Medical Science), Laboratory technician

I joined the Aouadi lab in Summer of 2017. I have had the opportunity to learn and gain practical experience in various techniques that are currently available and being developed in the lab, such as single-cell RNA sequencing and in situ sequencing. I have since then acquired multiple laboratory skills, and in my current role as a laboratory technician, I participate and assist in many of the ongoing research projects in the lab.

As my daily battle field is on the lab bench, my aspiration is to constantly solve the smaller research questions in a bigger research hypothesis, using the most recent and cutting-edge techniques that is made accessible in the dynamic and fast-paced research environment of the Aouadi lab. And as part of this lab, I hope to continue supporting the scientific research, as we strive towards the common goal of unraveling the underlying mechanisms of obesity and insulin resistance, and to ultimately improving human health.

Valerio AzzimatoValerio Azzimato, Postdoc

I obtained my PhD in Pharmacological Sciences from Università Statale di Milano in 2014. My research project focused on epigenetic mechanisms regulating intracellular communication in cardiovascular scenario. In 2015 I joined KI as a junior postdoc in order to investigate the interplay between DNA methylation, molecular pathways and metabolism in heart diseases. In February 2018, I joined Dr. Aouadi's group in order to study the role(s) of liver macrophages in the regulation of systemic metabolism. In this lab I have the opportunity to use state-of-the-art techniques to investigate the crosstalk between immune and metabolic cells. My aim is to better understand the molecular circuits responsible for the development of metabolic diseases.

Joost WillebrordsJoost Willebrords, Postdoc

I obtained a PhD in Pharmaceutical Sciences at the lab of In Vitro Toxicology and Dermato-Cosmetology at the Vrije Universiteit Brussel in Brussels (Belgium). There, I investigated the role of connexin and pannexin channels in non-alcoholic steatohepatitis, which is currently the most common chronic liver disease in the Western world. I also performed experiments at the University of São Paolo in Brazil as part of a double PhD diploma. As of April 2018, I conduct postdoctoral research in Dr. Aouadi´s group and focus on the further unravelling of cellular and molecular mechanisms in the development of metabolic diseases such as non-alcoholic steatohepatitis, diabetes and obesity.

I chose Dr. Aouadi´s group based on her great expertise in the emerging field of immunometabolism, which is expected to play a crucial role in non-alcoholic steatohepatitis. The study of this field requires the application of an array of techniques new to me, such as fluorescence-activated cell sorting, single cell RNA sequencing and glucan-encapsulated siRNA particles technology. The training of these techniques in the Aouadi group are thus of great value to my scientific career.

Alumni

Marcela Aparicio-Vergara, PhD, former postdoctoral fellow, now research manager of Nutrition & Health at NutriLeads, Netherlands.

Francisco Verdeguer, PhD, former postdoctoral fellow, now group leader at the University of Zurich.

Jennifer Jager, Principal Investigator at University of Nice, France.

Aouadi Lab at Twitter

Follow: @AouadiLab

[embed]<blockquote class="twitter-tweet" data-lang="sv"><p lang="en" dir="ltr">This year&#39;s Helmholtz Young Investigator in Diabetes Award (HeIDi) 2018 for the best upcoming researchers goes to: Myriam Aouadi, Ph.D. <a href="https://twitter.com/karolinskainst?ref_src=twsrc%5Etfw">@karolinskainst</a> und Fabiana Perocchi, Ph.D. HMGU. Congratulations!! <a href="https://twitter.com/hashtag/HelmholtzDiabetes2018?src=hash&amp;ref_src=…">#HelmholtzDiabetes2018</a> <a href="https://twitter.com/hashtag/Diabetesresearch?src=hash&amp;ref_src=twsrc…">#Diabetesresearch</a> <a href="https://twitter.com/helmholtz_diabc?ref_src=twsrc%5Etfw">@helmholtz_diabc</a> <a href="https://t.co/mlkjskATtj">pic.twitter.com/mlkjskATtj</a></p>&mdash; Helmholtz_Muenchen (@HelmholtzMucEn) <a href="https://twitter.com/HelmholtzMucEn/status/1045685707359080448?ref_src=t…">28 september 2018</a></blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>[/embed]

Selected publications

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