In the Infographic below, you can check ongoing Projects and find out intersections among the Research Topics for each project. You can access the Abstract and other information by clicking on any of these projects (P1-P16). Or you can find more about the Researchers by clicking on the initial letters of their names here:
The role of NAD+-dependent lysine deacetylases (sirtuins) and their inhibitors in Aspergillus fumigatus acetylome and virulence
Infectious Disease | Immune Mediated Diseases
Abstract In the past few years, invasive fungal infections have been among the major causes of mortality and morbidity in immunocompromised individuals. One and a half million deaths are estimated per year, being the Aspergillus fumigatus the main invasive aspergillosis agent. Characteristics such as morphogenetic changes, host adaptation, and antifungals resistance contribute to the fungus virulence. Isolates resistant to the main drugs used for the aspergillosis treatment, azole, echinocandins and amphotericin B, have often been reported. Studies indicate that changes in chromatin, essential for cellular adaptation to physiological and environmental changes, caused by histone lysine acetylation and deacetylation may act to control virulence and drug resistance characteristics. Moreover, several other non-histone proteins from different organisms involved in different biological processes, as oxidative stress response and metabolism, have been described to be acetylated, which are also targets for lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). This fact suggests that KAT and KDAC can be potentially targeted for new antifungals. Preliminary results indicate that the sirtuin (KDAC class III) inhibitors nicotinamide, sirtinol, and salermide showed significant effects on the growth reduction of the A. fumigatus Af293 strain. The aim of this study is to analyze the antifungal potential of KADC inhibitors in invasive aspergillosis caused by A. fumigatus and evaluate the expression profile of KDACs in A. fumigatus azole-resistant strains. In addition, A. fumigatus mutants of genes encoding sirtuins will be designed using the CRISPR-Cas9 system to understand their function and potential as new drug targets.
Influence of Sirtuins in the global gene expression and metabolites production in Aspergillus fumigatus
Infectious Disease | Metabolism
Abstract Invasive aspergillosis is a cause of great concern in public health. This is an infection that affects more than 200,000 people a year and is especially a threat to immunosuppressed or immunocompromised patients. The main agent of this type of infection is the filamentous fungus Aspergillus fumigatus and a few years ago, strains resistant to antifungals increased the concern regarding these infections. Polyenes, flucytosine, echinocandins and azoles are the classes of drugs available today for yeast infections. Azoles are the first line of treatment against aspergillosis, however, strains resistant to azoles have been identified globally. Post-translational modifications have been widely studied and related to several fungal cell characteristics. Among these changes, histone acetylations have been linked, for example, to the growth, development, virulence and reproduction of these organisms. This type of modification in histones is responsible for the activation or silencing of genes through the remodeling of chromatin. KATs (acetylases) and KDACs (deacetylases) are primarily responsible for this process and have been considered as possible targets for the treatment of azole-resistant fungal infections. Therefore, sirtuin-inhibiting compounds, a class of KDACs, have been the target of studies as potential coadjuvants associated with canonical drugs to treat fungal infections resistant to the main drugs. These inhibitors have been shown to be able to interfere with the growth and secondary metabolism of filamentous fungi. The objective here is to describe the relationship among sirtuins, the global gene expression and secondary metabolites production in A. fumigatus.
Role of the high-fiber diet on the function of the intestinal stem cells and their niche
Microbiota | Metabolism
Abstract Dietary fibers are fermented by the intestinal microbiota generating important metabolites known as short-chain fatty acids (SCFAs). These molecules act differently on various cell lineages: on intestinal epithelial cells, SCFAs regulate the pattern of histone modifications, an effect that is related to cell proliferation and cancer. The intestinal epithelium is a single-layer barrier composed by several cell types, all originated from the intestinal stem cells (ISCs) located at the bottom of the intestinal crypts. Although some studies demonstrated that different diet approaches regulate the function of the ISCs, the impact diets enriched in fiber on these cells is scarce. Thus, the aim of this project is to elucidate the role of a high fiber diets on the ISCs and their niche.
Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation
Microbiota | Infectious Diseases
Abstract How the microbiota communicates with the host and contributes to health is a key question for progress in this research field. Bacterial metabolites called short chain fatty acids (SCFAs), which are generated by fermentation of non-digestible carbohydrates, constitute a link between microbiota and host cells. Previous studies demonstrated that these metabolites regulate host metabolism and immunity. However, the molecular mechanisms are not totally defined. The aim of this project is to investigate the role of SCFA receptor FFAR2 (GPR43) and modifications of the pattern of histone acylations in neutrophils, innate lymphoid cells and intestinal epithelial cells (IECs) and their biological relevance in infectious/inflammatory models.
CAMeLEOm: Cross-Species Analysis of Metabolic, Lifespan Effects and Omics of Dietary Restriction Mimetics
Abstract The overarching aim of this proposal is to delineate the common molecular networks in adipose tissue involved in the lifespan and health promoting effects of dietary restriction and its mimetics such as dietary methionine restriction (MR) and dietary supplementation with nicotinamide riboside (NR) - a dairy constituent that maintains NAD metabolism. To achieve that, we designed a pipeline to sort out biologically relevant pathways affected by these interventions. Briefly, we will perform omics of samples obtained from C. elegans, and adipose tissue and serum of mice and humans (healthy and/or type 2 diabetic) subjected to DR or its mimetic interventions. We will correlate these findings with lifespan and/or metabolic profiling and use bioinformatics tools to identify evolutionary conserved pathways that are commonly affected by the dietary interventions. The relevant pathways will then be scrutinized using gain- or loss-of-function models in C. elegans, mice and mammalian preadipocyte cell lines, providing new insights into how these dietary interventions affect health span in multiple organisms, including humans. A collaboration with the University of Copenhagen.
Translational models and identification of new therapeutic targets in the field of adipose tissue biology, type 2 diabetes and non-alcoholic steatohepatitis
Metabolism | Immune-Mediated Diseases
Abstract The major goals of this project are to fill the gap of translational models and identify novel therapeutic targets in the areas of white/brown adipose tissue biology, T2D and NASH. A collaboration with AstraZeneca.
DecAI: Decoding Aging Initiative
Aging | Metabolism
Abstract A number of pathways have been shown to regulate animal lifespan and organismal aging. The Antebi lab has recently discovered the nucleolus as a crucial focal point for these pathways. The nucleolus is a subnuclear organelle dedicated to rRNA production and ribogenesis, which also controls other key processes in the RNA metabolism of the cell, including small RNA processing and assembly of ribonucleoproteins. miRNAs are a class of small non-coding RNAs which regulate gene expression at the post-transcriptional level and have been implicated in development, disease, and aging. We and others have shown that miRNAs can influence lifespan, and that they can exert their effects in a cell-non-autonomous fashion. Our investigation of miRNA regulation in aging and cell-non-autonomy gave rise to the initiation of the DecAl cooperation in 2018, a project funded by CAPES and DAAD to allow human resource exchange. Early results from this collaboration have revealed that loss-of-function mutations in a miRNA/siRNA processing enzyme, DICER, affect nucleolar size, thereby potentially also placing the nucleolus as a link between small RNAs and aging. In addition, we found that incubation of human Jurkat cells with serum of exercised mice reduces nucleolus size and that this effect is dependent on the presence of DICER in adipocytes, suggesting that nucleolus size is cell non-autonomously controlled by adipose tissue small RNAs in response to exercise training. Despite the mounting evidence, the extent and mechanism of this regulation remains unclear. The focus of this proposal is therefore to (1) identify genes and circulating factors that affect miRNA and siRNA processing and RNA metabolism in aging, and (2) map the processes through which this regulation occurs, with a particular focus on the nucleolus. A collaboration with the Max-Planck Institute for Biology of Ageing.
Exploring Mechanisms of Intercellular Communication in Obesity
Metabolism | Immune-Mediated Diseases
Abstract The overarching aim of this proposal is to identify new molecules that contribute to intercellular communication during obesity and insulin resistance. For that we specifically aim to: 1) identify molecules that are secreted by adipocytes or adipose tissue macrophages in conditions of altered energy balance; and 2) explore mechanisms of intercellular crosstalk in vitro. A project of the Obesity and Comorbidities Research Center.
Influence of the endocannabinoid system on the energetic profile of neural cells during neurodevelopment: implications in Schizophrenia
Metabolism | Associated Brain Disorders
Abstract Schizophrenia is a severe mental disorder, incapacitating and incurable that affects around 23 million people in the world. Among the hypotheses that try to explain the causes of Schizophrenia, the neurodevelopment hypothesis proposes that a combination of genetic and environmental disturbances since the development of the nervous system in utero are fundamental for the emergence of the disorder, that usually manifests itself in late adolescence/early adulthood. Several studies conducted on cerebral tissue from Schizophrenia patients collected postmortem point to dysfunctions in energy metabolism and mitochondrial processes. Recent results from our laboratory showed alterations in energy metabolism of Neural Stem Cells (NSC) and neurons derived from Induced Pluripotent Stem Cells (iPSC) from Schizophrenia patients, demonstrating that those alterations are observed during neurodevelopment. It is known that the modulation of the endocannabinoid system is important for key processes in neurodevelopment and can regulate neuronal bioenergetics. In this way, the present project proposes to derive cerebral organoids and neural cells from iPSC from Schizophrenia patients, recapitulating the processes that occur during neurodevelopment, and evaluate the situation of the energy and oxidative metabolism of those organoids and neural cells before and after treatment with cannabinoids.
Study of Metabolic Syndrome on clozapine treated adipocytes
Metabolism | Associated Brain Disorders
Abstract Schizophrenia is an incurable psychiatric illness that affects about 1% of the world's population. The symptoms usually appear in adult life and are divided into three categories: positive symptoms (hallucinations and delusions); negative symptoms (unsociability, depression and lack of motivation); and cognitive problems (difficulty concentrating, impaired executive functions and long-term memory failure). The treatment is usually performed with antipsychotics that are often inefficient or have many side effects. Clozapine is an antipsychotic known for its efficacy in relieving the symptoms of treatment-resistant patients. However, the drug can cause serious side effects and some patients may develop a metabolic syndrome, the most common symptoms of which include fast weight gain, cardiovascular problems and diabetes. Our project aims to treat human adipocytes with clozapine and to analyze 1) its proteomic profile in order to verify the biochemical pathways altered by the drug and 2) the expression profile of miRNAs, since the last have been described as endocrine signaling in tissue adipose. Our goal is to find molecular signatures that could elucidate the mechanisms of action by which clozapine causes metabolic syndrome in patients and, in the future, use that knowledge to associate the drug with the attenuating components and/or provide insights to improve the drug or even create a new drug.
Evaluating the effects of clozapine on immune system cells
Immune | Associated Brain Disorders
Abstract Schizophrenia is a heterogeneous and multifactorial disorder that affects around 21 million people worldwide. The disease is often characterized by the occurrence of positive, negative and cognitive symptoms. Several studies have shown that patients with schizophrenia present high concentrations of inflammatory molecules in the brain. These molecules could cross the blood brain barrier and change the homeostasis of the central nervous system. They can also interact with microglia, triggering an unsuitable inflammatory response in the brain, impairing the role of resident cells. Recent studies have revealed a decrease of microglia activation in animal models treated with clozapine. Although this antipsychotic is the main choice in refractory schizophrenia, clozapine can induce agranulocytosis as side effect, which may lead to death. Thus, here we are going to perform proteomic analyses of microglia cultures treated with the blood serum of schizophrenia patients, in addition to clozapine treatment, allowing the identification of key metabolic pathways to the disorder. The present project is also going to carry out proteomic analyses of clozapine-induced agranulocytosis in an ex vivo model, searching for potential therapeutic targets that could lead to the improvement of patients' health and quality of life.
From the basic understanding to clinical biomarkers to schizophrenia: a neuroproteomics-centered multidisciplinary study
Abstract Schizophrenia is among the most disabling diseases of humankind, affecting 1% of the world's population (in Brazil, almost 2.5 million people are affected). One of the biggest hurdles faced by most patients is the poor efficacy of current antipsychotic medication. This stems from the lack of understanding of schizophrenia's pathobiology and the lack of biomarkers and biological mechanisms associated with a positive medication response. By employing state-of-the-art proteomics and lipidomics in blood plasma collected in vivo from patients before and after treatment, we aim to identify predictive biomarkers for medication response. These will be used to compose a mass spectrometry-based molecular assay to aid psychiatrists in predicting the likelihood of a successful treatment before initiating medication. This will be the first clinical test ever developed to determine medication response in psychiatry. Moreover, by analyzing the proteomes and lipidomes of these blood plasma samples, we can also better understand the biochemistry and biology involved the response. To develop new and more effective medication, we must increase our understanding of the molecular aspects of schizophrenia. Therefore, we will test several of the biological hypotheses our group has built over the past few years. For that, we are moving to a multidisciplinary approach employing CRISPR/Cas9, flow cytometry, proteomics, phosphoproteomics, lipidomics, interactomics, transcriptomics, and miRNA expression in coordination with several laboratories in Brazil and abroad to characterize postmortem brains and peripheral mononuclear blood cells from patients and mentally healthy controls. In addition, pre-clinical models will also be evaluated, such as induced pluripotent stem cell-derived neurons and glial cells, cerebral organoids, and cell lines of neurons, glia, and adipocytes. We will search for the validation of the key biological processes we found associated with schizophrenia such as tripartite synapses, spliceosomes, myelination, and energy pathway-associated alterations, as well as the role of the endocannabinoid system in glia. Results from these studies may point to biological processes that could be modulated by new drugs yet to be developed. Our results will lead to three major benefits in the field: 1) refining a biochemical assay able to predict the efficacy of medications currently available to patients, even before the treatment starts; 2) identifying key biochemical pathways associated with effective medication; 3) and better comprehension of schizophrenia's molecular basis and biochemistry, which is key for developing new treatments. Our project navigates from basic to applied science, towards the establishment of translational strategies driven by personalized and precision medicine concepts, helping to bring the bench closer to the bedside.
Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases
Abstract The field of Immunometabolism is the new frontier for Immunology as it integrates the historically distinct disciplines of Metabolism and Immunology. The growing interest in Immunometabolism is fueled by the global obesity epidemic and the strong association between inflammation and metabolic disease. Obesity-induced inflammation is a risk factor for several chronic pathologies and diseases. Investigating how the metabolic status of the immune system is altered under obesogenic conditions will provide insight into new mechanisms and therapeutic targets underlying immunometabolic regulation and homeostasis. Central players regulating this metabolic crosstalk include the transcriptions factors HIF-1± (hypoxia induced factor 1±) and LXR (liver X receptor), and the metabolic sensor mTOR (mammalian target of rapamycin), specifically the complex 1 of mTOR characterized by Raptor and the complex 2 by Rictor. These proteins modulate important cellular immune responses and metabolic signaling, thereby affecting the metabolic status of both the host tissue and overall organism. Chronic disease states can affect the function of these proteins (HIF-1±, LXR and mTOR) to shift host cellular function to a new physiologic state. This project hypothesizes that the metabolic sensors regulate the metabolism and inflammatory function of macrophages and CD4 T cells. The objective is to determine how metabolism regulates the function of tissue resident macrophages and CD4 T cells under both physiologic and inflammatory states. Findings from this project will focus on the crosstalk between the metabolic and the immune systems to identify intersecting mechanisms underlying pathophysiological conditions including obesity and inflammatory diseases that may reveal promising molecular targets and novel therapeutic applications in humans.
The study and characterization of endogenous mammalian fatty acids hydroxy fatty acids as a novel drugs for the treatment of inflammatory and metabolic diseases
Metabolism | Immune-Mediated Diseases
Abstract Lipids or fatty acids are considered excellent sources of energy and novel information about unexpected fatty acid roles in physiologic and inflammatory processes has emerged and brought lipids into a new level of importance. Recently, we together with other researchers discovered a novel class of lipids that has not previously been described in mammalian tissues - fatty acyl hydroxy fatty acids (FAHFAs). Members of this lipid family are present in many tissues and in serum of normal mice and humans. Certain fatty acids are natural ligands for cell surface receptors and nuclear receptors and they act as signaling molecules that regulate physiological functions as diverse as insulin secretion, inflammation, and hepatic glucose production. The overall goal of this proposal is to determine the biologic role(s) of FAHFA family members. We found one FAHFA to be the most potent anti-inflammatory action. We will quantify the levels of these specific FAHFA, named FAHFA-1 in serum and multiple tissues and in resident immune cells and determine their regulation in genetic and dietary mouse models of obesity-induced insulin resistance. We will next determine if FAHFA-1 is taken up into cells and if cells secrete them by using labeled 13C FAHFA-1 and 13C Hydroxy Stearic Acid (HAS). Also, we will investigate the effects of FAHFA-1 on inflammatory pathways and metabolic regulation of macrophages. Finally, we will determine the receptor for FAHFA-1 and investigate if it is a ligand for cell surface receptors and/or nuclear receptors. We will investigate binding to cell surface receptor(s) using biotinylated FAHFA-1. The discovery of any novel metabolite, such as FAHFAs, indicates the existence of uncharted biochemical pathways and enzymes that control metabolism in cells, tissues and organisms. We plan to garner information about new pathways that regulate FAHFA levels and we will discover the receptor responsible for FAHFA effects in vivo. This could lead to a novel treatment for type 2 diabetes.
Mitoimmunity: Mitochondria adaptation in pathological and physiological states
Abstract The biochemical of activities occurring in mitochondria are linked to mitochondria morphology. For example, the spatial segregation of biochemical pathways ultimately controls oxidative phosphorylation and energy generation. Systemic and tissue-derived cues shape mitochondria through fission/fusion events, which orchestrates how mitochondria will function. In the immune system, effector cells, such as macrophages, must rapidly alter their metabolism according to extrinsic cues such as cytokines and microbial products, to acquire different phenotypes and functional states necessary for the downstream function. For example, bacterial activated macrophages can produce nitric oxide to kill pathogens while other macrophages favor wound healing and tissue repair. Activated, macrophages have increased metabolic demands closely linked to mitochondria bioenergetics. In model systems, mitochondrial function is closely linked to mitochondria morphology. Systemic and tissue-derived cues shape mitochondria number and function through fission/fusion events, which orchestrates how mitochondria will function. However, in macrophages, almost nothing is known about the relationships between mitochondrial morphology, their adaptive metabolic functions and how mitochondrial dynamics are linked to immune outcomes. Therefore, the overall goal of this project is to determine how mitochondria dynamics regulates macrophage phenotype and function in both on physiological and pathological situations. The proposal is divided into three main objectives. First, we will determine how changes in mitochondria fusion/fission alters macrophage phenotype and function and also the role of nitric oxide in this process and the pathways involved. Second, we will determine how changes in mitochondria fusion/fission alters monocyte/macrophage phenotype and function in humans. Third, we will determine how mitochondria dynamics influences the outcome of infectious (Leishmaniasis) and metabolic (obesity-induced insulin resistance) diseases. This unpaved area of research will bring new insights into the field of immunometabolism to further our knowledge into dynamic mitochondria-mediated regulation of macrophages in comparison to our more detailed understanding of mitochondria dynamics in non-immune cells. This project offers new insights into how macrophage mitochondria dynamics regulate the outcomes auto-inflammatory, metabolic and infectious diseases with great potential for patient wellbeing, as macrophage metabolism is linked to virtually every acute and chronic disease.
The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing
Abstract The world population is getting older and older. Unfortunately, this increased life expectancy is generally associated by so-called age-related vascular diseases, such as dementia, heart infarct, and stroke, which profoundly compromise the quality of life of the elderly. Age-related disorders are generally viewed as necessary evil. This project challenges this dogma, as we propose that the aforementioned age-related disorders, despite their very diverse symptom profiles, share vascular ageing as common denominator. Moreover vascular ageing is caused by cumulative by accumulation of unrepaired DNA damage and mitochondrial dysfunction in the vessel wall which both increase with age. These events interplay and induce progressive senescence, inflammation and function loss of the vessel wall, which eventually will manifest as cardiovascular dysfunction or neurodegeneration, two very important hallmarks of ageing. Several of the predominant human diseases, such as obesity, diabetes and cardiovascular diseases, are directly related to this chain of cellular and physiological events that are part of and accelerate the process of ageing. This proposal joins experts on DNA damage repair, mitochondrial dysfunction, inflammation and cardiovascular disease to deploy and share knowledge and knowhow to unravel this common disease axis. To do so they will combine cutting edge technologies (e.g. scRNASEq, MitoNGS. CRISPR-Cas, organoids, MacroScreen functionomics platform, (intravital or multispectral) imaging and process reporters) with unique cellular and mouse models, deficient in processes that lead to accelerated ageing phenotypes. The insights gained in this project will be harnessed to the design of new (metabolic) biomarkers of vascular ageing and for novel therapeutic measures to revert this deleterious axis. By targeting a unique common mechanism in vascular ageing we expect that this project will help to reduce these age-related diseases thus improving quality of life for the elderly, and bringing the vista of healthy ageing within reach.
Determining molecular candidates that contribute to the higher risk of COVID-19 in aged individuals
Aging │ Metabolism
Abstract COVID-19 has recently emerged as an age-related disease whose mechanisms are still poorly understood. Using a combination of hypothesis-oriented and unsupervised, data-driven approaches, as well as patients and pre-clinical models, we expect to come up with candidate proteins and pathways which could not only predict the susceptibility to the disease, but also unveil the molecular mechanisms through which aging contributes to SARS-Cov-2 infection. We also expect to provide candidate FDA and ANVISA approved drugs which could potentially target these pathways to prevent, mitigate or eliminate virus infection. Our overarching aim is to elucidate how aging constitutes the main risk factor for COVID-19, providing potential solutions to its pandemic.