Cholesterol Regulation in Age-Related Macular Degeneration: A Framework for Mathematical Modelling of Drusen Biogenesis

Scheepers, Ronél; Pettet, Graeme J.; Heijster, Peter van; Araujo, Robyn P.

doi:10.1007/s11538-020-00812-0

Cited by 5 publications

(6 citation statements)

References 71 publications

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“…They capture the aggregation of lipofuscin granules, though they do not link this to RPE cell death. Zekavat et al [304] and Scheepers et al [258] have developed compartmental ODE models for drusen and cholesterol accumulation. The models capture features such as the build-up of drusen and their macrophage-mediated elimination, and determine regions of parameter space in which a healthy homeostasis may be maintained.…”

Section: Non-namdmentioning

confidence: 99%

Advancing treatment of retinal disease through in silico trials

2023

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Treating retinal diseases to prevent sight loss is an increasingly important challenge. Thanks to the configuration of the eye, the retina can be examined relatively easily in situ. Owing to recent technological development in scanning devices, much progress has been made in understanding the structure of the retina and characterising retinal biomarkers. However, treatment options remain limited and are often of low efficiency and efficacy.In recent years, the concept of in silico clinical trials has been adopted by many pharmaceutical companies to optimise and accelerate the development of therapeutics. In silico clinical trials rely on the use of mathematical models based on the physical and biochemical mechanisms underpinning a biological system. With appropriate simplifications and assumptions, one can generate computer simulations of various treatment regimens, new therapeutic molecules, delivery strategies and so forth, rapidly and at a fraction of the cost required for the equivalent experiments. Such simulations have the potential not only to hasten the development of therapies and strategies but also tooptimise the use of existing therapeutics.In this paper, we review the state-of-the-art in in silico models of the retina for mathematicians, biomedical scientists and clinicians, highlighting the challenges to developing in silico clinical trials. Throughout this paper, we highlight key findings from in silico models about the physiology of the retina in health and disease. We describe the main building blocks of in silico clinical trials and identify challenges to developing in silico clinical trials of retinal diseases.

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Section: Non-namdmentioning

confidence: 99%

Advancing treatment of retinal disease through in silico trials

2023

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“…A proportion of cholesterol in the ER is converted to cholesterol esters (CE) by the ER enzyme acylcoenzyme A (CoA):cholesterol acyltransferase (ACAT) (Chang et al, 2006(Chang et al, , 2009. Newly synthesised CE accumulates within the rough ER and buds off as cytoplasmic lipid droplets, whereby it acts as a reservoir from which its hydrolysis can mobilise unesterified cholesterol for steroid hormone, oxysterols or bile acid production (Scheepers et al, 2020;Chang et al, 2009;Simons and Ikonen, 2000).…”

Section: Cholesterol Fluxmentioning

confidence: 99%

“…Glycosphingolipids and cholesterol are central players in lipid raft biology (Sonnino and Prinetti, 2013;Grassi et al, 2020), and considering the impacts of disrupted lipid raft composition, the total cellular level of cholesterol and its distribution between membranes, and within a given membrane, must be precisely controlled (Simons and Ikonen, 2000). Furthermore, as a macronutrient, cholesterol plays an integral role in the synthesis of steroid hormones and vitamin D, while dysregulated cholesterol metabolism can lead to pathophysiological diseases such age-related macular degeneration and cardiovascular disease (Scheepers et al, 2020;Curcio et al, 2011;Mc Auley and Mooney, 2014).…”

Section: Introductionmentioning

confidence: 99%

Robust Homeostasis of Cellular Cholesterol via Antithetic Integral Control

Scheepers

Araujo

2023

Preprint

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Although cholesterol is essential for cellular viability and proliferation, it is highly toxic in excess. The concentration of cellular cholesterol must therefore be maintained within tight tolerances and is thought to be subject to a stringent form of homeostasis known as Robust Perfect Adaptation (RPA). While much is known about the cellular signalling interactions involved in cholesterol regulation, the specific chemical reaction network structures that might be responsible for the robust homeostatic regulation of cellular cholesterol have been entirely unclear until now. In particular, the molecular mechanisms responsible for sensing excess whole-cell cholesterol levels have not been identified previously, and no mathematical models to date have been able to capture an integral control implementation that could impose RPA on cellular cholesterol. Here we provide a detailed mathematical description of cholesterol regulation pathways in terms of biochemical reactions, based on an extensive review of experimental and clinical literature. We are able to decompose the associated chemical reaction network structures into several independent subnetworks, one of which is responsible for conferring RPA on several intracellular forms of cholesterol. Remarkably, our analysis reveals that RPA in the cholesterol concentration in the endoplasmic reticulum (ER) is almost certainly due to a well-characterised control strategy known as antithetic integral control which, in this case, involves the high-affinity binding of a multi-molecular transcription factor complex with cholesterol molecules that are excluded from the ER membrane. Our model provides a detailed framework for exploring the necessary biochemical conditions for robust homeostatic control of essential and tightly regulated cellular molecules such as cholesterol.

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“…In the healthy human eye, vision is accomplished through phototransduction, where photoreceptors in the neural retina receive and transmit visual stimuli to the brain for subsequent processing (Scheepers et al 2020). The neural retina is a complex sensory tissue found in the posterior part of the eye and lies above a single layer of post-mitotic cuboid cells called the retinal pigment epithelium (RPE) (Fig.…”

Section: Introductionmentioning

confidence: 99%

A distributed integral control mechanism for the regulation of cholesterol concentration in the human retina

Scheepers,

Levi,

Araujo

2024

Preprint

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Tight homeostatic control of cholesterol concentration within the complex tissue microenvironment of the retina is a hallmark of the healthy eye. By contrast, dysregulation of the biochemical mechanisms governing retinal cholesterol homeostasis is thought to be a major contributor to the aetiology and progression of age-related macular degeneration (AMD) in the ageing human eye. Although the signalling mechanisms that contribute to cholesterol homeostasis at the cellular level have been studied extensively, there is currently no systems-level description of the molecular interactions that could explain cholesterol homeostasis at the level of the human retina. Here were provide a comprehensive overview of all currently-known molecular-level interactions involved in the regulation of cholesterol across all major compartments of the human retina, encompassing the retinal pigment epithelium (RPE), the photoreceptor cell layer, the Müller cell layer, and Bruch’s membrane. We develop a detailed chemical reaction network (CRN) of this complex collection of biochemical interactions, comprising seventy-one (71) molecular species, which we show may be partitioned into ten (10) independent subnetworks. These ten subnetworks work together to confer robust homeostasis on thirteen different forms of cholesterol distributed through distinct cellular compartments of the retina. Remarkably, we provide compelling evidence thatthree independentantithetic integral controllers are responsible for the tight regulation of endoplasmic reticulum (ER) cholesterol in retinal cells, and that severaladditional independentmechanisms transfer this homeostatic property to other forms of cholesterol throughout the human retina. Our novel and exquisitely detailed mathematical description of retinal cholesterol regulation provides a framework for considering potential mechanisms of cholesterol dysregulation in the diseased eye, and for the study of potential therapeutic strategies against these pathologies.

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Cholesterol Regulation in Age-Related Macular Degeneration: A Framework for Mathematical Modelling of Drusen Biogenesis

Cited by 5 publications

References 71 publications

Advancing treatment of retinal disease through in silico trials

Advancing treatment of retinal disease through in silico trials

Robust Homeostasis of Cellular Cholesterol via Antithetic Integral Control

A distributed integral control mechanism for the regulation of cholesterol concentration in the human retina

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