Browsing by Subject "Preclinical models"

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    A novel murine model of combined insulin-dependent diabetes and chronic kidney disease has greater skeletal detriments than either disease individually
    (Elsevier, 2022-12) Damrath, John G.; Metzger, Corinne E.; Allen, Matthew R.; Wallace , Joseph M.; Anatomy, Cell Biology and Physiology, School of Medicine
    Diabetes and chronic kidney disease (CKD) consistently rank among the top ten conditions in prevalence and mortality in the United States. Insulin-dependent diabetes (IDD) and CKD each increase the risk of skeletal fractures and fracture-related mortality. However, it remains unknown whether these conditions have interactive end-organ effects on the skeleton. We hypothesized that combining IDD and CKD in mice would cause structural and mechanical bone alterations that are more deleterious compared to the single disease states. Female C57BL6/J mice were divided into four groups: 1) N=12 Control (CTRL), 2) N=10 Streptozotocin-induced IDD (STZ), 3) N=10 Adenine diet-induced CKD (AD), and 4) N=9 Combination (STZ+AD). STZ administration resulted in significantly higher blood glucose, HbA1c (p<0.0001), and glucose intolerance (p<0.0001). AD resulted in higher blood urea nitrogen (p=0.0002) while AD, but not STZ+AD mice, had high serum parathyroid hormone (p<0.0001) and phosphorus (p=0.0005). STZ lowered bone turnover (p=0.001). Trabecular bone volume was lowered by STZ (p<0.0001) and increased by AD (p=0.003). Tissue mineral density was lowered by STZ (p<0.0001) and AD (p=0.02) in trabecular bone but only lowered by STZ in cortical bone (p=0.002). Cortical porosity of the proximal tibia was increased by AD, moment of inertia was lower in both disease groups, and most cortical properties were lower in all groups vs CTRL. Ultimate force, stiffness, toughness, and total displacement/strain were lowered by STZ and AD. Fracture toughness was lower by AD (p=0.003). Importantly, Cohen’s D indicated that STZ+AD most strongly lowered bone turnover and mechanical properties. Taken together, structural and material-level bone properties are altered by STZ and AD while their combination resulted in greater detriments, indicating that improving bone health in the combined disease state may require novel interventions.
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    Brain metabolic network covariance and aging in a mouse model of Alzheimer's disease
    (Wiley, 2024) Chumin, Evgeny J.; Burton, Charles P.; Silvola, Rebecca; Miner, Ethan W.; Persohn, Scott C.; Veronese, Mattia; Territo, Paul R.; Medicine, School of Medicine
    Introduction: Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a human and financial impact for which few effective drugs exist to treat the disease. Advances in molecular imaging have enabled assessment of cerebral glycolytic metabolism, and network modeling of brain region have linked to alterations in metabolic activity to AD stage. Methods: We performed 18 F-FDG positron emission tomography (PET) imaging in 4-, 6-, and 12-month-old 5XFAD and littermate controls (WT) of both sexes and analyzed region data via brain metabolic covariance analysis. Results: The 5XFAD model mice showed age-related changes in glucose uptake relative to WT mice. Analysis of community structure of covariance networks was different across age and sex, with a disruption of metabolic coupling in the 5XFAD model. Discussion: The current study replicates clinical AD findings and indicates that metabolic network covariance modeling provides a translational tool to assess disease progression in AD models.