References of "Brady, Nathan"
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See detailROS homeostasis in a dynamic model: How to save PD neuron?
Kolodkin, Alexey UL; Ignatenko, Andrew UL; Sangar, Vineet et al

Poster (2014, December)

Detailed reference viewed: 173 (14 UL)
See detailROS-activated signaling network: dynamic modelling and design principles study
Kolodkin, Alexey UL; Ignatenko, Andrew UL; Sangar, Vineet et al

Poster (2014, June)

Detailed reference viewed: 178 (11 UL)
See detailDynamic modelling of ROS management and ROS-induced mitophagy
Kolodkin, Alexey UL; Ignatenko, Andrew UL; Sangar, Vineet et al

Poster (2014, June)

Detailed reference viewed: 158 (16 UL)
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See detailDesign principles study of ROS management and ROS-induced mitophagy with a kinetic model
Kolodkin, Alexey UL; Ignatenko, Andrew UL; Sangar, Vineet et al

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 ▲]

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Peer Reviewed
See detailModeling cellular ROS defense in mitochondrial-related diseases
Simeonidis, Vangelis UL; Kolodkin, Alexey UL; Ignatenko, Andrew UL et al

Poster (2013, July 22)

Reactive Oxygen Species (ROS) generation is an unavoidable background process during normal cellular function. The main contributor to ROS production is the electron transport chain, which reduces oxygen ... [more ▼]

Reactive Oxygen Species (ROS) generation is an unavoidable background process during normal cellular function. The main contributor to ROS production is the electron transport chain, which reduces oxygen to water. Some incompletely-reduced oxygen species escape and oxidize a variety of organic molecules, leading to molecular dysfunction and initiating a positive feedback loop of ever increasing active radical production. The increased concentration of ROS damages the mitochondria, therefore further elevating the rate of ROS generation. Healthy cells manage ROS enzymatically and by mitophagy of damaged mitochondria. The precise tuning of the latter mechanism is crucial for cell survival and is controlled by a ROS-induced regulatory network. We have built a set of kinetic models of varying complexity, based on the current understanding of the mechanism of cellular ROS defense. Our models allow simulation of various patho-physiological scenarios related to mitochondrial dysfunction and the failure of the system of ROS regulation in human cells. We employ the models we have constructed to simulate the effects of diseases related to mitochondrial dysfunction and excessive ROS generation, such as Parkinson’s disease, Huntington’s disease and cancer. Experimental evidence is used for model fitting, and we propose model improvements based on incorporation of single-cell experimental measurements. Finally, we discuss the perspective of integrating our kinetic models with genome-scale, constraint-based, tissue-specific models of metabolism, in order to study the effect of ROS misregulation on metabolic phenotype. [less ▲]

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See detailROS-induced regulation of mitophagy and its failure in Parkinson’s disease
Kolodkin, Alexey UL; Ignatenko, Andrew UL; Simeonidis, Vangelis UL et al

Poster (2013, May)

Reactive Oxygen Species (ROS) generation is an unavoidable background process in the normal functioning of the cell. The greatest contributor to ROS production is the electron transport chain (ETC) where ... [more ▼]

Reactive Oxygen Species (ROS) generation is an unavoidable background process in the normal functioning of the cell. The greatest contributor to ROS production is the electron transport chain (ETC) where O2 is reduced to H2O. Some incompletely-reduced oxygen species escape and oxidize a variety of organic molecules (e.g. proteins and lipids in the mitochondrial membrane), leading to molecular dysfunction and initiating a positive feedback loop leading to generation of even more active radicals. Increased ROS concentration damages mitochondria and further increases ROS generation. Healthy cells manage ROS enzymatically with superoxide dismutase and other enzymes, various antioxidants, and ultimately through increased mitophagy of damaged mitochondria. The precise tuning of the latter mechanism is crucial for cell survival and is controlled in the cell by a ROS-induced regulatory network, which consists of many components such as Nrf2, Keap1, Parkin and p62 with a rather complicated cross-talk (Figure 1). In many diseases (cancer, Parkinson’s disease (PD), Huntington’s disease (HD), etc.), various components of the ROS management network are altered. Deconstructing the molecular mechanisms underlying or resulting from these alterations might contribute to better understanding of the dynamics of related pathophysiological processes. We have built a kinetics-based model which recapitulates the consensus understanding of the mechanism responsible for cellular ROS – managing system. [less ▲]

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See detailA kinetic model and design principles study of cellular ROS defence and its failure in Parkinson’s disease
Kolodkin, Alexey UL; Simeonidis, Vangelis UL; Brady, Nathan et al

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 ▲]

Detailed reference viewed: 181 (1 UL)