Thesis (Ph. D.)--University of Wisconsin--Madison, 1954. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 119-122).

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfdment of the requirements for the degree of Doctor of Philosophy / Asthma is a complex syndrome which has a significant inflammatory basis which results from the complex interactions between heterogenous genetic and environmental factors. Although the environmental allergens are fairly well known, little information concerning the genetic differences between atopic and non-atopic individuals is available. Alpha-1 antitrypsin is the archetypal member of the serine proteinase inhibitor or serpin superfamily and the most important proteinase inhibitor in the lung with specificity to neutrophil elastase. Genetic deficiency of the protein is classically associated with early onset emphysema, bronchiecstasis, panniculitis, rheumatoid arthritis and glomerulonephritis. The S(E264V), Z(E342K), Ml (213 Ala) and M2 (R101H) variants of alpha-1 antitrypsin have been implicated in the pathogenesis of asthma. A novel finding was the identification of 2 new variants, the M1E(JOhannesburg) and the M IN(johannesburg) associated with asthma in individuals from South Africa / IT2018

Dissertation (Ph.D.).--University of Texas Graduate School of Biomedical Sciences at San Antonio, 2008. / Vita. Includes bibliographical references.

Reactive oxygen species (ROS), and the resulting oxidative stress caused by these species, have long been attributed to be one of the causes for aging and age related disorders. NADPH, the reduced form of nicotinamide adenine dinucleotide phosphate (NADP), provides a critical and essential buffer against cellular toxicity due to ROS. NADPH is one of the cells most powerful reducing agents, capable of regenerating other endogenous antioxidants such as glutathione from its oxidized form, glutathione disulfide. Consequently, it is hypothesized that declining NADPH levels with age results in a depletion in cellular capacity to respond to ROS induced damage, further accelerating the aging process. To study the importance of NADPH on the aging process as well as the molecular mechanisms involved, lifespan assays were performed using knockdown of various enzymes involved in the production of NADPH in Caenorhabditis elegans. Preliminary results indicate declining NADPH levels do have an effect on expected longevity. More interesting however, is a possibly important distinction between cytoplasmic and mitochondrial enzymes involved in the production of NADPH. These preliminary results suggest the existence of a previously undescribed molecular mechanism that is potentially important to the aging process. However, further experiments and analysis are required to further elucidate these mechanisms and to confirm preliminary findings.

<p>Obesity is associated with a state of chronic, low-grade inflammation that contributes to the development of insulin resistance. Exercise is known to improve insulin resistance, and emerging evidence suggests that exercise also reduces adipose tissue inflammation. However, the relationship between exercise and inflammation has not been separated from the confounding effect of weight loss. The objectives of this study were to 1) determine whether high-intensity interval training (HIT) improves insulin sensitivity in obese mice independent of weight loss and 2) assess the effect of exercise on the relationship between adipose tissue inflammation and insulin sensitivity.</p> <p>C57BL/6 mice were assigned to one of three groups: a control, chow diet (Chow), 12 weeks of high-fat diet with no exercise (HFD Sed), or 6 weeks of high-fat diet feeding followed by an additional 6 weeks of HIT (HFD Ex). In HFD-induced obese mice, HIT had no effect on body mass, epididymal fat mass, adiposity, or adipocyte size. HIT also did not alter adipose tissue inflammation, macrophage infiltration, or adipose tissue macrophage polarization/inflammation. Nevertheless, when compared to HFD Sed mice, HIT resulted in lower fasting insulin levels and improved glucose tolerance and insulin sensitivity.</p> <p>In conclusion, these finding demonstrate that HIT improves whole-body insulin sensitivity and glucose homeostasis independent of changes in body mass or adipose tissue inflammation. The benefits of exercise in obese individuals are obvious; however, the mechanisms underlying the improvements in insulin sensitivity observed following chronic, HIT remain to be elucidated.</p> / Master of Science (MSc)

<p>In obesity, nonalcoholic fatty liver disease (NAFLD) has been associated with the development of hepatic insulin resistance. Acetyl coA carboxylase (ACC), which exists as two separate isoforms (ACC1 and ACC2), is an important metabolic enzyme which controls the production of the metabolic intermediate malonyl coA, and hence, fat metabolism. AMP-activated protein kinase (AMPK) has been shown to inhibit ACC activity by phosphoryating ACC1 at Ser79 and ACC2 at Ser221. The objectives of this were to determine the physiological importance of AMPK phosphorylation of ACC as it relates to the development of NAFLD and insulin resistance.</p> <p>We examined the metabolic phenotype of C57Bl6 mice with a targeted ACC1 Ser79 to Ala and ACC2 Ser221 to Ala double knock-in mutation (ACC DKI), which would inhibit AMPK phosphorylation of ACC and compared them to wild-type (WT) mice. Basic body characteristics, assessment of insulin sensitivity, and assessment of liver steatosis were used.</p> <p>ACC DKI body mass and energy expenditure were not different compared to WT. Liver ACC activity and malonyl coA were higher in ACC DKI mice. The livers of ACC DKI mice displayed greater triacylglycerol accumulation and aggregation of neutrophils. ACC DKI mice were insulin resistant as shown by: higher fasting blood glucose and insulin, glucose and insulin intolerance, liver insulin resistance, and impaired insulin-stimulated glucose disposal rate.</p> <p>In summary, we have shown that the phosphorylation of ACC1 Ser79 and ACC2 Ser221 is critical for maintaining ACC activity and malonyl coA levels in the liver. The dysregulation of this pathway results in liver fat accumulation and the development of insulin resistance. These studies demonstrate that AMPK phosphorylation of ACC is essential for maintaining metabolic homeostasis.</p> / Master of Science (MSc)

<p>Maternal obesity is associated with an increased risk of pregnancy complications, including preeclampsia, miscarriage, birth of small for gestational age (SGA) babies, and stillbirth. Placental dysfunction has been implicated in all of these complications; however, the mechanisms by which maternal obesity influences placental development and function are not well understood. Female Sprague-Dawley rats were fed either a control diet (CON; 16% kcal from fat) or a high fat diet (HF; 45% kcal from fat) for 16 weeks beginning at weaning and were then mated with age-matched CON-fed males. This model emulates life-long obesity prior to pregnancy, a situation which is clinically relevant. Prior to pregnancy, HF-fed dams were 36% heavier and had significantly more abdominal fat. Dams were sacrificed at either gestational day (GD) 15 or GD18 to collect placental tissues. The remaining females were allowed to give birth naturally. HF-fed dams showed evidence of increased intrauterine death at GD15 and GD18. At birth, smaller litter sizes, offspring with reduced birthweight, and more stillbirths were observed in the HF-fed group. Placentas from HF-fed dams exhibited morphological changes at GD15, including an increased area covered by the labyrinth zone, an increase in blood vessel density and decrease in blood vessel maturity in the labyrinth layer, as well as increased carbonic anhydrase staining, indicative of hypoxia. These changes were associated with increased vascular endothelial growth factor (VEGF) protein levels and decreased placental growth factor (PlGF) protein levels. Both interstitial and endovascular trophoblast invasion into the maternal mesometrial triangles were increased at GD15. While these differences were no longer evident by GD18, placental morphometry demonstrated that the area covered by the labyrinth layer remained significantly greater in the HF-fed compared to CON-fed dams. Placental oxidative stress, which is often associated with placental dysfunction, was not observed at statistically significant levels at GD15. The early dysregulation of placental structure in HF-fed dams, which is normalized later in gestation, may play a role in the development of pregnancy complications associated with maternal obesity.</p> / Master of Science (MSc)

<p>The association between low birth weight at <em>term </em>birth and an increased risk for insulin resistance (IR) in adulthood is well established. Less is known about this association in those born markedly <em>preterm</em>. Lower birth weights are more prevalent among individuals born preterm. We compared and examined determinants of IR in adults born preterm with extremely low birth weight (ELBW; birth weight</p> / Master of Health Sciences (MSc)

<p>End stage renal disease (ESRD) has been a world-wide cause of renal disease-related fatality. Most patients with ESRD progress through chronic kidney disease (CKD). There are various causes of CKD including mechanical stress, infections, high blood pressure or immune conditions. Renal fibrosis is known to play an important pathogenic role in CKD and ESRD. Transforming growth factor-beta (TGF-ß) is one of the major mediators of fibrosis, and inhibition of TGF-ß could reduce renal fibrosis in in vitro models. One of the well - known inducers of TGF-ß transcr iption is Angiotensin II (ANGII). 1 This is a major contributor to the matrix accumulation and glomerular fibrosis leading to a decline in kidney function and kidney failure in patients with chronic kidney disease (CKD). 2 A recent study demonstrated that TGF -ß could be increased by SREBP -1c overexpression. 3 My laboratory’ s data showed that ANGII could induce TGF-ß on a transcriptional level, and this induction could be block ed by Fatostatin, an SREBP/SCAP inhibitor. My data showed that ANGII could induce SREBP-1 in a time and dose dependent manner. Therefore my study focused on understanding the role of SREBP-1 in ANGII-induced TGF-ß upregulation in primary mesangial cells (MCs). We found that ANGII- induced TGF-ß promoter activity requires Angiotensin type 1 receptor (AT1R) and SREBP-1 activation as well as ER stress. Interestingly , the activation of SREBP-1 by ANGII stimulation relies on ER stress and PI3K/AKT signaling. Both ANGII and ER stress inducer s could induce AKT phosphorylation, indicat ing that ER stress is an upstream mediator in th is signaling pathway. We also found that ER stress inhibit ion could block SREBP-1 activation by ANGII stimulation and, more importantly , could also block ANGII- induced TGF-ß promoter activity. In C57BL/6 mice infused with ANGII for one week, we found that both SREBP-1 and GRP78 were significantly upregulated in glomeruli in the ANGII infusion group compared with the control group. Taken together , this data indicates that ER stress is required for SREBP-1 activation, both of which are mediators of kidney fibrosis.</p> / Master of Science (MSc)

<p>Mitochondrial dysfunction has been linked to a number of age-associated disorders and recent evidence has shown that mitochondrial function is necessary for osteoblast differentiation and osteoclast survival. Although bone tissue was once thought to be an ‘inert’ tissue, research from the past decade in bone metabolism has demonstrated pathways linking bone and whole body energy metabolism. However, with mitochondria being the central energy provider in cells there is a paucity of research exploring the impact of mitochondrial function on bone tissue, with the bulk of work focused in cell culture. This thesis aimed to explore mitochondrial content and function after endurance training and an exhaustive bout of running in two different animal models. The first study explored the effect of progressive mitochondrial dysfunction on mitochondrial gene expression and bone strength in the polymerase gamma mouse model of mitochondrial dysfunction. The therapeutic efficacy of endurance training on mitochondrial parameters and bone strength were evaluated as well. The second study utilized the Koch-Britton rat model of low capacity and high capacity runners. This model has demonstrated that selection for low and high running capacity has led to a significant divergence in mitochondrial content and function between these two groups. Mechanical strain in the form of exercise has been established as playing a key role in regulating bone health however the underlying mechanisms are still being described. The untrained status and inherent differences in aerobic capacity allow for the elucidations of bone adaptations that may be a result of aerobic capacity. The effect of an exhaustive bout of exercise on mitochondrial gene expression and enzyme activity in LCR and HCR rats was studied. Taken together these studies demonstrate that exercise is beneficial for promoting bone health and may do so by altering mitochondrial content and stress resistance through the FoxO family of transcription factors.</p> / Doctor of Philosophy (Medical Science)