Biomedical Engineering Department Theses and Dissertations

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Browsing Biomedical Engineering Department Theses and Dissertations by Author "Allen, Matthew"

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    The Skeletal Phenotype Of The Kk/Ay Murine Model Of Type 2 Diabetes
    (2022-08) Chowdhury, Nusaiba Nahola; Wallace, Joseph; Allen, Matthew; Bone, Robert; Na, Sungsoo
    Type-2-diabetes (T2D) is a progressive metabolic disease characterized by insulin resistance and β-cell dysfunction leading to persistent hyperglycemia. It is a multisystem disease that causes deterioration of multiple organ systems and obesity. Of interest, T2D affects the urinary system and is the leading cause of kidney disease. Both T2D and chronic kidney negatively impacts the skeletal system and increases fracture incidence in patients. Therefore, it is important to establish an animal model that captures the complex multiorgan effects that is common in T2D. In this study, we characterized the metabolic phenotype of the KK/Ay mouse model, a polygenic mutation model of T2D. We concluded that KK/Ay mice closely mimic T2D and are hyperglycemic, hyperinsulinemic and insulin resistant. KK/Ay mice have also had worsened kidney function as supported by elevated levels of blood urea nitrogen, phosphorous, creatinine, and calcium in plasma exhibiting the kidney’s inefficiency in clearing waste from the body. Even though we were able to confirm a metabolic phenotype for T2D and diabetic nephropathy, the skeletal effects of the disease were minimal and major differences in bone physiology were driven by sex differences. This study offered valuable insight into preliminary endpoints for the KK/Ay mouse mode that will decide the direction for future use of this model. We plan to use older mice in future studies to allow a longer time for skeletal effects to more prominently manifest.
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    Targeting Bone Quality in Murine Models of Osteogenesis Imperfecta, Diabetes, and Chronic Kidney Disease
    (2024-05) Kohler, Rachel; Wallace, Joseph; Allen, Matthew; Bidwell, Joseph; Surowiec, Rachel
    Skeletal fragility can be caused by a wide array of diseases and disorders, but the most difficult etiologies to clinically circumvent are those in which the body loses not just bone mass but the ability to create healthy bone tissue. While in conditions such as osteoporosis (the most prevalent cause of age-related skeletal fragility in which elevated resorption without compensatory elevated formation leads to bone loss), interventions can target bone remodeling pathways to protect and increase bone mass, many other diseases are characterized by genetic and metabolic crippling of the remodeling process, rendering those same mass-based interventions less effective at reducing fracture risk. Osteogenesis imperfecta (OI) is a class of genetic disorders in which gene mutations affect the formation of collagen, a crucial building block of bone tissue that makes up 90% of its organic matrix, leading to lost bone mass and quality. As the main genetic causes of OI cannot currently be directly treated, therapeutic OI treatments are needed that improve tissue-level material properties. Similarly, metabolic conditions such as diabetes, a disorder in which the body cannot properly regulate blood sugar due to loss of insulin production and/or efficacy, can have multi-organ impacts including increased risk of developing chronic kidney disease and skeletal fragility. Type 2 diabetes is especially notorious for increasing fracture risk despite maintained or even increased apparent bone mass, which is strong evidence that intrinsic bone material properties are impaired by the disease state. A possible solution to the bone quality problem may be treatments that increase bone water content, as amplifying the water content of bone can improve multi-scale material properties such as collagen fibril elasticity and whole-bone toughness. Therefore, increasing bone hydration could be a way of improving tissue-level material properties, despite being unable to eradicate the genetic or metabolic disorders that alter how collagen is produced and incorporated into the bone matrix. To that end, this dissertation presents several studies that characterize models of osteogenesis imperfecta and diabetic kidney disease in mice and investigate methods of rescuing skeletal fragility in these animals through treatments that target both bone mass and bone quality with ties to tissue hydration.