ROS-activated signaling network: dynamic modelling and design principles study

Poster (2014, June)

Systems medicine approaches for the definition of complex phenotypes in chronic diseases and ageing. From concept to implementation and policies.

in Current pharmaceutical design (2014), 20(38), 5928-44

Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health ... [more ▼]

Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health) represent the predominant health problem of the Century. The prevention and control of NCDs are the priority of the World Health Organization 2008 Action Plan, the United Nations 2010 Resolution and the European Union 2010 Council. The novel trend for the management of NCDs is evolving towards integrative, holistic approaches. NCDs are intertwined with ageing. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has prioritised NCDs. To tackle them in their totality in order to reduce their burden and societal impact, it is proposed that NCDs should be considered as a single expression of disease with different risk factors and entities. An innovative integrated health system built around systems medicine and strategic partnerships is proposed to combat NCDs. It includes (i) understanding the social, economic, environmental, genetic determinants, as well as the molecular and cellular mechanisms underlying NCDs; (ii) primary care and practice-based interprofessional collaboration; (iii) carefully phenotyped patients; (iv) development of unbiased and accurate biomarkers for comorbidities, severity and follow up of patients; (v) socio-economic science; (vi) development of guidelines; (vii) training; and (viii) policy decisions. The results could be applicable to all countries and adapted to local needs, economy and health systems. This paper reviews the complexity of NCDs intertwined with ageing. It gives an overview of the problem and proposes two practical examples of systems medicine (MeDALL) applied to allergy and to NCD co-morbidities (MACVIA-LR, Reference Site of the European Innovation Partnership on Active and Healthy Ageing). [less ▲]

Design principles study of ROS management and ROS-induced mitophagy with a kinetic model

Poster (2013, September 27)

In vivo evidence demonstrates three fundamental interconnected adaptive survival mechanisms , which protect against excessive ROS that is generated during mitochondrial dysfunction: (i) autophagy ... [more ▼]

In vivo evidence demonstrates three fundamental interconnected adaptive survival mechanisms , which protect against excessive ROS that is generated during mitochondrial dysfunction: (i) autophagy/mitophagy, (ii) adaptive antioxidant response and (iii) NFkB signaling in cancer and neurodegeneration. We have been expanding a kinetic model which recapitulates the consensus understanding of the mechanisms responsible for cellular ROS – management system and performed modular analysis to analyze emergent behavior. We started with the simplest model and added stepwise new modules. We identify the qualitative role (certain emergent behavior) attributed to each module and thus understand the design principles of the system. We propose a detailed, mechanistic, kinetic model for studying how mutations relevant for diseases such as PD and cancer affect the emergent behavior of ROS management network. [less ▲]

The hallmarks of Parkinson's disease.

in FEBS Journal (2013)

Since the discovery of dopamine as a neurotransmitter in the 1950s, Parkinson's disease (PD) research has generated a rich and complex body of knowledge, revealing PD to be an age-related multifactorial ... [more ▼]

Since the discovery of dopamine as a neurotransmitter in the 1950s, Parkinson's disease (PD) research has generated a rich and complex body of knowledge, revealing PD to be an age-related multifactorial disease, influenced by both genetic and environmental factors. The tremendous complexity of the disease is increased by a non-linear progression of the pathogenesis between molecular, cellular, and organic systems. In this mini-review, we explore the complexity of PD and propose a systems-based approach, organizing the available information around cellular disease hallmarks. We encourage our peers to adopt this cell-based view with the aim of improving communication in interdisciplinary research endeavors targeting the molecular events, modulatory cell-to-cell signaling pathways, and emerging clinical phenotypes related to PD. This article is protected by copyright. All rights reserved. [less ▲]

Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an ... [more ▼]

Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amounts of itaconic acid, a metabolite previously proposed to have an antimicrobial effect. We purified IRG1 protein and identified its cis-aconitate decarboxylating activity in an enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial growth under specific conditions. Here we show that itaconic acid inhibits the growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages resulted in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections. Taken together, our results demonstrate that IRG1 links cellular metabolism with immune defense by catalyzing itaconic acid production. [less ▲]

Network analysis for systems biology

in Prokop, Aleš; Csukás (Eds.) Springer book in Systems Biology, Vol.1: Systems Biology:, Integrative Biology and Simulation Tools (2013)

Network analysis is an essential component of systems biology approaches toward understanding the molecular and cellular interactions underlying biological systems functionalities and their perturbations ... [more ▼]

Network analysis is an essential component of systems biology approaches toward understanding the molecular and cellular interactions underlying biological systems functionalities and their perturbations in disease. Regulatory and signalling pathways, which involve DNA, RNA proteins and metabolites as key elements, coordinate most aspects of cellular functioning. Cellular processes, which are dependent on the structure and dynamics of gene regulatory networks, can be studied by employing a network representation of molecular interactions. In this chapter we describe several types of networks and how combination of different analytic approaches can be used to study diseases. We provide a list of selected tools for visualization and network analysis. We introduce protein-protein interaction networks, gene regulatory networks, signalling networks and metabolic networks. We then define concepts underlying network representation of cellular processes and molecular interactions. We finally discuss how the level of accuracy in inferring functional relationships influences the choice of methods applied for the analysis of a particular network type. [less ▲]

Computational infrastructures for data and knowledge management in systems biology

in Prokop, Ales; Csukás, Bela (Eds.) Systems Biology: Integrative Biology and Simulation Tools (2013)

The volume, complexity and heterogeneity of data originating from high throughput functional genomics technologies have created challenges and opportunities for Information Technology (IT) departments ... [more ▼]

The volume, complexity and heterogeneity of data originating from high throughput functional genomics technologies have created challenges and opportunities for Information Technology (IT) departments. These increased demands have also led to increasing costs for IT infrastructure such as necessary computing power and storage devices, as well as further costs for manpower effort, required for maintenance. This chapter describes some of the challenges for computational analysis infrastructure, including bottlenecks and most pressing needs that have to be addressed to effectively support the development of systems biology and its application in medicine. [less ▲]

Functional Genomics, Proteomics, Metabolomics and Bioinformatics for Systems Biology

in Prokop, Ales; Csukás, Bela (Eds.) Systems Biology: Integrative Biology and Simulation Tools (2013)

This chapter introduces systems biology, its context, aims, concepts and strategies. It then describes approaches and methods used for collection of high-dimensional structural and functional genomics ... [more ▼]

This chapter introduces systems biology, its context, aims, concepts and strategies. It then describes approaches and methods used for collection of high-dimensional structural and functional genomics data, including epigenomics, transcriptomics, proteomics, metabolomics and lipidomics, and how recent technological advances in these fields have moved the bottleneck from data production to data analysis and bioinformatics. Finally, the most advanced mathematical and computational methods used for clustering, feature selection, prediction analysis, text mining and pathway analysis in functional genomics and systems biology are reviewed and discussed in the context of use cases. [less ▲]

On different aspects of network analysis in systems biology

in Systems Biology (2013), 1

Network analysis is an essential component of systems biology approaches toward understanding the molecular and cellular interactions underlying biological systems functionalities and their perturbations ... [more ▼]

Network analysis is an essential component of systems biology approaches toward understanding the molecular and cellular interactions underlying biological systems functionalities and their perturbations in disease. Regulatory and signalling pathways involve DNA, RNA, proteins and metabolites as key elements to coordinate most aspects of cellular functioning. Cellular processes depend on the structure and dynamics of gene regulatory networks and can be studied by employing a network representation of molecular interactions. This chapter describes several types of biological networks, how combination of different analytic approaches can be used to study diseases, and provides a list of selected tools for network visualization and analysis. It also introduces protein-protein interaction networks, gene regulatory networks, signalling networks and metabolic networks to illustrate concepts underlying network representation of cellular processes and molecular interactions. It finally discusses how the level of accuracy in inferring functional relationships influences the choice of methods applied for the analysis of a particular biological network type. © Springer Science+Business Media Dordrecht 2013. All rights are reserved. [less ▲]

A kinetic model and design principles study of cellular ROS defence and its failure in Parkinson’s disease

Poster (2012, August)

Mitochondrial generation of reactive oxygen species (ROS) is an unavoidable side effect of oxidative phosphorylation. To counteract the production of ROS, the cell employs two main strategies. The first ... [more ▼]

Mitochondrial generation of reactive oxygen species (ROS) is an unavoidable side effect of oxidative phosphorylation. To counteract the production of ROS, the cell employs two main strategies. The first one is to increase the consumption of ROS; this mechanism involves the superoxide dismutase enzyme and various antioxidants. The second strategy is to reduce the production of ROS by decreasing mitochondrial membrane potential and by increasing mitophagy. The precise tuning of the latter is crucial for cell survival: if mitophagy is too active, all mitochondria are lost and the cell suffers from reduced ATP capacity; if mitophagy is not active enough, dysfunctional mitochondria accumulate, more ROS is produced, and the cell undergoes unwanted programmed cell death. We hypothesize that a ROS-activated regulatory network is employed to coordinate the regulation of the rate of mitophagy, the expression of uncoupling proteins and the production of antioxidants, including SOD. In Parkinson’s disease (PD), the activities of several components of this regulatory network (e.g. KEAP1, PARK7, VDAC1, SQSTM1) are altered. This makes the cell susceptible to ROS damage. In the case of dopaminergic neurons, this effect can be particularly severe, because an additional pool of non-mitochondrial ROS generated during ROS-induced degradation of dopamine. In order to understand the functioning of the ROS-activated regulatory network in normal function and disease, we have built a kinetic model. Our model includes 39 species and 45 reactions, with 56 kinetic parameters, either fitted or obtained from literature. Our model allows the simulation of PD-related ROS generation and mitochondrial damage and the identification of the design principles underlying the functioning of the network; for example, showing and explaining the synergy between the down-regulation of both VDAC1 and PARK7 occurring during PD. The kinetic model has great potential use for better understanding of the pathophysiology of PD and for the suggestion of novel mitochondria-related PD treatments. [less ▲]