Applications of Boolean modelling to study and stratify dynamics of a complex disease

Interpretation of omics data is needed to form meaningful hypotheses about disease mechanisms. Pathway databases give an overview of disease-related processes, while mathematical models give qualitative and quantitative insights into their complexity. Similarly to pathway databases, mathematical models are stored and shared on dedicated platforms. Moreover, community-driven initiatives such as disease maps encode disease-specific mechanisms in both computable and diagrammatic form using dedicated tools for diagram biocuration and visualisation. To investigate the dynamic properties of complex disease mechanisms, computationally readable content can be used as a scaffold for building dynamic models in an automated fashion. The dynamic properties of a disease are extremely complex. Therefore, more research is required to better understand the complexity of molecular mechanisms, which may advance personalized medicine in the future. In this study, Parkinson’s disease (PD) is analyzed as an example of a complex disorder. PD is associated with complex genetic, environmental causes and comorbidities that need to be analysed in a systematic way to better understand the progression of different disease subtypes. Studying PD as a multifactorial disease requires deconvoluting the multiple and overlapping changes to identify the driving neurodegenerative mechanisms. Integrated systems analysis and modelling can enable us to study different aspects of a disease such as progression, diagnosis, and response to therapeutics. Therefore, more research is required to better understand the complexity of molecular mechanisms, which may advance personalized medicine in the future. Modelling such complex processes depends on the scope and it may vary depending on the nature of the process (e.g. signalling vs metabolic). Experimental design and the resulting data also influence model structure and analysis. Boolean modelling is proposed to analyse the complexity of PD mechanisms. Boolean models (BMs) are qualitative rather than quantitative and do not require detailed kinetic information such as Petri nets or Ordinary Differential equations (ODEs). Boolean modelling represents a logical formalism where available variables have binary values of one (ON) or zero (OFF), making it a plausible approach in cases where quantitative details and kinetic parameters 9 are not available. Boolean modelling is well validated in clinical and translational medicine research. In this project, the PD map was translated into BMs in an automated fashion using different methods. Therefore, the complexity of disease pathways can be analysed by simulating the effect of genomic burden on omics data. In order to make sure that BMs accurately represent the biological system, validation was performed by simulating models at different scales of complexity. The behaviour of the models was compared with expected behavior based on validated biological knowledge. The TCA cycle was used as an example of a well-studied simple network. Different scales of complex signalling networks were used including the Wnt-PI3k/AKT pathway, and T-cell differentiation models. As a result, matched and mismatched behaviours were identified, allowing the models to be modified to better represent disease mechanisms. The BMs were stratified by integrating omics data from multiple disease cohorts. The miRNA datasets from the Parkinson’s Progression Markers Initiative study (PPMI) were analysed. PPMI provides an important resource for the investigation of potential biomarkers and therapeutic targets for PD. Such stratification allowed studying disease heterogeneity and specific responses to molecular perturbations. The results can support research hypotheses, diagnose a condition, and maximize the benefit of a treatment. Furthermore, the challenges and limitations associated with Boolean modelling in general were discussed, as well as those specific to the current study. Based on the results, there are different ways to improve Boolean modelling applications. Modellers can perform exploratory investigations, gathering the associated information about the model from literature and data resources. The missing details can be inferred by integrating omics data, which identifies missing components and optimises model accuracy. Accurate and computable models improve the efficiency of simulations and the resulting analysis of their controllability. In parallel, the maintenance of model repositories and the sharing of models in easily interoperable formats are also important

Aging and Health

Aging is a major risk factor for chronic diseases, which in turn can provide information about the aging of a biological system. This publication serves as an introduction to systems biology and its application to biological aging. Key pathways and processes that impinge on aging are reviewed, and how they contribute to health and disease during aging is discussed. The evolution of this situation is analyzed, and the consequences for the study of genetic effects on aging are presented. Epigenetic programming of aging, as a continuation of development, creates an interface between the genome and the environment. New research into the gut microbiome describes how this interface may operate in practice with marked consequences for a variety of disorders. This analysis is bolstered by a view of the aging organism as a whole, with conclusions about the mechanisms underlying resilience of the organism to change, and is expanded with a discussion of circadian rhythms in aging

Role of adipose tissue in the pathogenesis and treatment of metabolic syndrome

© Springer International Publishing Switzerland 2014. Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrate organisms. Excess adipocyte size or number is a hallmark of obesity, which is currently a global epidemic. Obesity is not only the primary disease of fat cells, but also a major risk factor for the development of Type 2 diabetes, cardiovascular disease, hypertension, and metabolic syndrome (MetS). Today, adipocytes and adipose tissue are no longer considered passive participants in metabolic pathways. In addition to storing lipid, adipocytes are highly insulin sensitive cells that have important endocrine functions. Altering any one of these functions of fat cells can result in a metabolic disease state and dysregulation of adipose tissue can profoundly contribute to MetS. For example, adiponectin is a fat specific hormone that has cardio-protective and anti-diabetic properties. Inhibition of adiponectin expression and secretion are associated with several risk factors for MetS. For this purpose, and several other reasons documented in this chapter, we propose that adipose tissue should be considered as a viable target for a variety of treatment approaches to combat MetS

A Knowledge-based Integrative Modeling Approach for <em>In-Silico</em> Identification of Mechanistic Targets in Neurodegeneration with Focus on Alzheimer’s Disease

Dementia is the progressive decline in cognitive function due to damage or disease in the body beyond what might be expected from normal aging. Based on neuropathological and clinical criteria, dementia includes a spectrum of diseases, namely Alzheimer's dementia, Parkinson's dementia, Lewy Body disease, Alzheimer's dementia with Parkinson's, Pick's disease, Semantic dementia, and large and small vessel disease. It is thought that these disorders result from a combination of genetic and environmental risk factors. Despite accumulating knowledge that has been gained about pathophysiological and clinical characteristics of the disease, no coherent and integrative picture of molecular mechanisms underlying neurodegeneration in Alzheimer’s disease is available. Existing drugs only offer symptomatic relief to the patients and lack any efficient disease-modifying effects. The present research proposes a knowledge-based rationale towards integrative modeling of disease mechanism for identifying potential candidate targets and biomarkers in Alzheimer’s disease. Integrative disease modeling is an emerging knowledge-based paradigm in translational research that exploits the power of computational methods to collect, store, integrate, model and interpret accumulated disease information across different biological scales from molecules to phenotypes. It prepares the ground for transitioning from ‘descriptive’ to “mechanistic” representation of disease processes. The proposed approach was used to introduce an integrative framework, which integrates, on one hand, extracted knowledge from the literature using semantically supported text-mining technologies and, on the other hand, primary experimental data such as gene/protein expression or imaging readouts. The aim of such a hybrid integrative modeling approach was not only to provide a consolidated systems view on the disease mechanism as a whole but also to increase specificity and sensitivity of the mechanistic model by providing disease-specific context. This approach was successfully used for correlating clinical manifestations of the disease to their corresponding molecular events and led to the identification and modeling of three important mechanistic components underlying Alzheimer’s dementia, namely the CNS, the immune system and the endocrine components. These models were validated using a novel in-silico validation method, namely biomarker-guided pathway analysis and a pathway-based target identification approach was introduced, which resulted in the identification of the MAPK signaling pathway as a potential candidate target at the crossroad of the triad components underlying disease mechanism in Alzheimer’s dementia

Aging and Health

Aging is a major risk factor for chronic diseases, which in turn can provide information about the aging of a biological system. This publication serves as an introduction to systems biology and its application to biological aging. Key pathways and processes that impinge on aging are reviewed, and how they contribute to health and disease during aging is discussed. The evolution of this situation is analyzed, and the consequences for the study of genetic effects on aging are presented. Epigenetic programming of aging, as a continuation of development, creates an interface between the genome and the environment. New research into the gut microbiome describes how this interface may operate in practice with marked consequences for a variety of disorders. This analysis is bolstered by a view of the aging organism as a whole, with conclusions about the mechanisms underlying resilience of the organism to change, and is expanded with a discussion of circadian rhythms in aging

High-Fat High-Saturated Diet

Dietary fat quality is a crucial determinant of several physiological, biochemical and molecular processes in the body, tissues and cells. As a source of energy, Fatty Acids (FA) are mainly stored in fat cells and within lipid droplets (LD) in oxidative and steroidogenic tissues, but significant amounts are also found in cell membranes where their structural role is crucial for membrane protein functions and the control of cellular functions. Differential effects have been identified between different types FA on inflammatory and metabolic diseases during obesity or in response to physical exercise and chronic diseases. The most recent dietary guidelines advise that lipids should represent 35% of the daily energy intake in order to prevent deleterious effects of high glycaemic index carbohydrates and deficiency in essential fatty acids. Hence, the prevalence of obesity could rise dramatically despite a fall in total fat intake. Advice is more focused on the improvement of the quality of fat than on the reduction of total fat intake. Dietary fat sources provide a mixture of saturated FA (SFA), monounsaturated FA (MUFA) and polyunsaturated FA (PUFA). Most institutional dietary guidelines claim that the consumption of SFA should be limited to the expense of MUFA and PUFA as a nutritional strategy for the prevention of chronic diseases. The role of dietary SFA and MUFA in cardiometabolic risk remains controversial in the scientific community. This special issue was proposed to publish articles that bring new elements into the topic by collecting recent advances for students and professionals involved in lipid and health

Longitudinal imaging of pancreatic islets transplanted into the anterior chamber of the eye

Diabetes is a growing health problem associated with substantial health and socioeconomic costs. Current medications address hyperglycaemia and related complications, but a definitive cure for diabetes remains elusive. Pharmacotherapy with the potential to restore β-cell function is urgently needed. To this end, it is vital that we achieve a better understanding of islet function in both health and disease states. While major breakthroughs in diabetes research have traditionally resulted from in vitro experimentation, the crucial role of the pancreatic internal milieu is being increasingly recognised. The islet in the eye imaging platform is the first experimental tool which allows for the longitudinal and direct investigation of β-cell function in a non-invasive manner. This thesis describes the application of this imaging platform to three divergent areas of islet research. Firstly the physiology of co-ordinated insulin secretion is examined. Pulsatile insulin secretion is physiologically relevant and is impaired in diabetes. The imaging platform is used to establish, for the first time in vivo, that the calcium waves that underlie insulin secretion arise from the co-ordinated activity of a heterogeneous group of β-cells. Obesity is the greatest risk factor for developing Type 2 diabetes. The effects of high fat diet on islet calcium dynamics are incompletely understood. Hyperglucagonaemia is traditionally thought of as a contributing factor to diabetes disease progression. Emerging evidence however suggests that glucagon signalling has beneficial effects on food intake and energy expenditure. More recently, the insulin potentiating effects of intra-islet glucagon has been suggested. The imaging platform is developed to investigate the longitudinal effects of high fat diet and the subsequent weight-loss independent effects of a synthetic glucagon analogue on islet function. Together, these two studies investigate the utility of the islet in the eye imaging platform to better our understanding of intercellular β-cell calcium dynamics in the acute and in a more chronic setting. Islet transplantation has not provided a reliable cure for patients with Type 1 diabetes, due to a relative lack of suitable donors but, more importantly, because the majority of patients fail to achieve long term insulin independence. The reasons for transplant failure are manifold and poorly 9 understood, although engraftment failure is a major issue. There is a clear need to improve transplant success rates, especially if this can be achieved in line with a more reliable supply of β-cells/islets (for example stem-cell derived therapies). The last experimental chapter aims to investigate the effects of epidermal growth factor receptor (EGFR) overexpression in β-cells and whether this treatment improves islet engraftment. In particular, this chapter focuses on the angiogenesis of newly transplanted islets and whether the islet in eye platform is capable of longitudinally monitoring this process.Open Acces

Bayesian Network Modeling and Inference in Plant Gene Networks And Analysis of Sequencing and Imaging Data

Scientific and technological advancements over the years have made curing, preventing or managing all diseases, a goal that seems to be within reach. The approach to manipulating biological systems is multifaceted. This dissertation focuses on two problems that pose fundamental challenges in developing methods to control biological systems: the first is to model complex interactions in biological systems; the second is faithful representation and analysis of biological data obtained from scientific equipments. The first part of this dissertation is a discussion on modeling and inference in gene networks, and Bayesian inference. Then we describe the application of Bayesian network modeling to represent interactions among genes, and integrating gene expression data in order to identify potential points of intervention in the gene network. We conclude with a summary of evolving directions for modeling gene interactions. The second topic this dissertation focuses on is taming biological data to obtain actionable insights. We introduce the challenges in representation and analysis of high throughput sequencing data and proceeds to describe the analysis of imaging data in the dynamic environment of cancer cells. Then we discuss tackling the problem of analyzing high throughput RNA sequencing data in order to pinpoint genes that exhibit different behaviors under monitored experimental conditions. Then we address the interesting problem of deciphering and quantifying gene-level activity from epifluorescent imaging data