Biology subjects

Versypt, A. N. F.

Publications and source records attributed to Versypt, A. N. F..

3 recordsLinked to original sources

bioRxiv2024

Effects of Disease on Renal Blood Flow Regulation: Assessing Autoregulation Disruption

The functioning of kidneys on blood flow regulation was investigated, particularly under diseased conditions such as chronic kidney disease, which includes conditions of diabetic nephropathy and other glomerular damage. A mathematical model was developed to better understand how variations based on the glomerular filtration rate impact key kidney function outputs, such as afferent arteriolar diameter, smooth muscle activation, and the chloride ion concentration at the macula densa. We have analyzed these factors by considering the dynamics of the mathematical model of ordinary and partial differential equations to study blood flow control in the kidney, which has provided new insights into the maintenance of autoregulation. By simulating the processes of renal blood flow--specifically through the afferent arteriole and glomerulus, and detailing the process of chloride transport within the renal tubule--the model offers a comprehensive view of how the kidney regulates glomerular filtration rate amidst fluctuating systemic blood pressures and disease-specific changes. Central to this model are the myogenic response that adjusts afferent arteriole muscle tone in reaction to pressure changes and the tubuloglomerular feedback, which controls arteriole size based on chloride levels at the macula densa. The models simulations reveal the robustness of renal autoregulation across a spectrum of chronic kidney disease stages, showing stability under normal conditions but indicating a breakdown in regulation with advanced chronic kidney disease. This breakdown is attributed to disruptions in the vascular and feedback systems. The findings from this model shed light on the progression of renal dysfunction in chronic kidney disease and underscore the potential for developing targeted treatments to maintain kidney health.

physiology↗

bioRxiv2023

Logic-Based Modeling of Inflammatory Macrophage Crosstalk with Glomerular Endothelial Cells in Diabetic Kidney Disease

Diabetic kidney disease is a complication in one out of three patients with diabetes. Aberrant glucose metabolism in diabetes leads to structural and functional damage in glomerular tissue and a systemic inflammatory immune response. Complex cellular signaling is at the core of metabolic and functional derangement. Unfortunately, the mechanism underlying the role of inflammation in glomerular endothelial cell dysfunction during diabetic kidney disease is not fully understood. Mathematical models in systems biology allow the integration of experimental evidence and cellular signaling networks to understand mechanisms involved in disease progression. This study developed a logic-based ordinary differential equations model to study inflammatory crosstalk between macrophages and glomerular endothelial cells during diabetic kidney disease progression using a protein signaling network stimulated with glucose and lipopolysaccharide. This modeling approach reduced the biological parameters needed to study signaling networks. The model was fitted to and validated against available biochemical data from in vitro experiments. The model identified mechanisms for dysregulated signaling in macrophages and glomerular endothelial cells during diabetic kidney disease. In addition, the influence of signaling interactions on glomerular endothelial cell morphology through selective knockdown and downregulation was investigated. Simulation results showed that partial knockdown of VEGF receptor 1, PLC-{gamma}, adherens junction proteins, and calcium partially recovered the intercellular gap width between glomerular endothelial cells. These findings contribute to understanding signaling and molecular perturbations that affect the glomerular endothelial cells in the early stage of diabetic kidney disease. NEW & NOTEWORTHYThe work provides a novel analysis of signaling crosstalk between macrophages and glomerular endothelial cells in the early stage of diabetic kidney disease. A logic-based mathematical modeling approach identified vital signaling molecules and interactions that regulate glucose-mediated inflammation in the glomerular endothelial cells and cause endothelial dysfunction in the diabetic kidney. Simulated interactions among vascular endothelial growth factor receptor 1, nitric oxide, calcium, and junction proteins significantly affect the intercellular gap between glomerular endothelial cells.

systems biology↗

bioRxiv2022

An agent-based modeling approach for lung fibrosis in response to COVID-19

The severity of the COVID-19 pandemic has created an emerging need to investigate the long-term effects of infection on patients. Many individuals are at risk of suffering pulmonary fibrosis due to the pathogenesis of lung injury and impairment in the healing mechanism. Fibroblasts are the central mediators of extracellular matrix (ECM) deposition during tissue regeneration, regulated by anti-inflammatory cytokines including transforming growth factor beta (TGF-{beta}). The TGF-{beta}-dependent accumulation of fibroblasts at the damaged site and excess fibrillar collagen deposition lead to fibrosis. We developed an open-source, multiscale tissue simulator to investigate the role of TGF-{beta} sources in the progression of lung fibrosis after SARS-CoV-2 exposure, intracellular viral replication, infection of epithelial cells, and host immune response. Using the model, we predicted the dynamics of fibroblasts, TGF-{beta}, and collagen deposition for 15 days post-infection in virtual lung tissue. Our results showed variation in collagen area fractions between 2% and 40% depending on the spatial behavior of the sources (stationary or mobile), the rate of activation of TGF-{beta}, and the duration of TGF-{beta} sources. We identified M2 macrophages as primary contributors to higher collagen area fraction. Our simulation results also predicted fibrotic outcomes even with lower collagen area fraction when spatially-localized latent TGF-{beta} sources were active for longer times. We validated our model by comparing simulated dynamics for TGF-{beta}, collagen area fraction, and macrophage cell population with independent experimental data from mouse models. Our results showed that partial removal of TGF-{beta} sources changed the fibrotic patterns; in the presence of persistent TGF-{beta} sources, partial removal of TGF-{beta} from the ECM significantly increased collagen area fraction due to maintenance of chemotactic gradients driving fibroblast movement. The computational findings are consistent with independent experimental and clinical observations of collagen area fractions and cell population dynamics not used in developing the model. These critical insights into the activity of TGF-{beta} sources may find applications in the current clinical trials targeting TGF-{beta} for the resolution of lung fibrosis. Author summaryCOVID-19 survivors are at risk of lung fibrosis as a long-term effect. Lung fibrosis is the excess deposition of tissue materials in the lung that hinder gas exchange and can collapse the whole organ. We identified TGF-{beta} as a critical regulator of fibrosis. We built a model to investigate the mechanisms of TGF-{beta} sources in the process of fibrosis. Our results showed spatial behavior of sources (stationary or mobile) and their activity (activation rate of TGF-{beta}, longer activation of sources) could lead to lung fibrosis. Current clinical trials for fibrosis that target TGF-{beta} need to consider TGF-{beta} sources spatial properties and activity to develop better treatment strategies.

bioengineering↗