Browsing by Author "Layton, Anita T."

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Aging affects circadian clock and metabolism and modulates timing of medication
(Elsevier, 2021-04) Sadria, Mehrshad; Layton, Anita T.
Aging is associated with impairments in the circadian rhythms, and with energy deregulation that affects multiple metabolic pathways. The goal of this study is to unravel the complex interactions among aging, metabolism, and the circadian clock. We seek to identify key factors that inform the liver circadian clock of cellular energy status and to reveal the mechanisms by which variations in food intake may disrupt the clock. To address these questions, we develop a comprehensive mathematical model that represents the circadian pathway in the mouse liver, together with the insulin/IGF-1 pathway, mTORC1, AMPK, NAD+, and the NAD+ -consuming factor SIRT1. The model is age-specific and can simulate the liver of a young mouse or an aged mouse. Simulation results suggest that the reduced NAD+ and SIRT1 bioavailability may explain the shortened circadian period in aged rodents. Importantly, the model identifies the dosing schedules for maximizing the efficacy of anti-aging medications.
Impact of sex and pathophysiology on optimal drug choice in hypertensive rats: Quantitative insights for precision medicine
(Elsevier, 2021-04) Ahmed, Sameed; Sullivan, Jennifer C.; Layton, Anita T.
Less than half of all hypertensive patients receiving treatment are successful in normalizing their blood pressure. Despite the complexity and heterogeneity of hypertension, the current antihypertensive guidelines are not tailored to the individual patient. As a step toward individualized treatment, we develop a quantitative systems pharmacology model of blood pressure regulation in the spontaneously hypertensive rat (SHR) and generate sex-specific virtual populations of SHRs to account for the heterogeneity between the sexes and within the pathophysiology of hypertension. We then used the mechanistic model integrated with machine learning tools to study how variability in these mechanisms leads to differential responses in rodents to the four primary classes of antihypertensive drugs. We found that both the sex and the pathophysiological profile of the individual play a major role in the response to hypertensive treatments. These results provide insight into potential areas to apply precision medicine in human primary hypertension.
Sex differences in solute and water handling in the human kidney: Modeling and functional implications
(Elsevier, 2021-06) Hu, Rui; McDonough, Alicia A.; Layton, Anita T.
The kidneys maintain homeostasis by controlling the amount of water and electrolytes in the blood. That function is accomplished by the nephrons, which transform glomerular filtrate into urine by a transport process mediated by membrane transporters. We postulate that the distribution of renal transporters along the nephron is markedly different between men and women, as recently shown in rodents. We hypothesize that the larger abundance of a renal Na+ transport in the proximal tubules in females may also better prepare them for the fluid retention adaptations required during pregnancy and lactation. Also, kidneys play a key role in blood pressure regulation, and a popular class of anti-hypertensive medications and angiotensin converting enzymes (ACE) inhibitors have been reported to be less effective in women. Model simulations suggest that the blunted natriuretic and diuretic effects of ACE inhibition in women can be attributed, in part, to their higher distal baseline transport capacity.