Ph.D. - Physiology

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    Comparative Study of TRPM5 in Pancreatic ß-Cells of Wistar Kyoto and Goto Kakizaki Rats
    ([Honolulu] : [University of Hawaii at Manoa], [May 2015], 2015-05) Monteilh-Zoller, Mahealani
    TRPM5 is a member of the melastatin subfamily of the Transient-Receptor-Potential superfamily of ion channels. Through functional analysis of the chromosomal region 11p15.5, TRPM5 was identified and linked to a variety of childhood and adult tumors as well as to Beckwith-Wiedemann syndrome (Prawitt et al., 2000). TRPM5 RNA has been detected in a variety of tissues including: taste receptor cells, small intestines, liver, lungs, testis and brain (Hofmann et al., 2003). In addition, the rat insulinoma (INS- 1) pancreatic ß-cell line was shown to endogenously express TRPM5 (Prawitt et al., 2003). While earlier studies of TRPM5 conducted in taste receptor cells report TRPM5 as a divalent cation channel that is activated through a G protein-coupled receptor/phospholipase C signaling pathway (Perez et al., 2002; Zhang et al., 2003), other studies (Hofmann et al., 2003; Liu and Liman, 2003) have characterized TRPM5 as a Ca2+-activated non-selective monovalent cation channel. I here, hypothesize that the pancreatic ß-cells of Goto Kakizaki will exhibit a reduction in TRPM5 which may contribute to the dysfunction of the ß-cell. To this end, we utilized immunostaining to compare the endogenous expression of TRPM5 in the Wistar Kyoto and Goto Kakizaki (spontaneous non-obese type 2 diabetes model) rat pancreatic ß-cell. We also incorporated the whole-cell patch technique to examine the activation characteristics of TRPM5 in both populations of rat ß-cells. Being that TRPM5 is Ca2+-activated, we included fura-2 Ca2+ measurements to connect intracellular Ca2+- signaling to TRPM5 activation. In addition, we utilized the perforated patch technique to study glucose-stimulated Ca2+-signaling and TRPM5 activation. Our results show TRPM5 expression in Wistar Kyoto rat pancreatic ß-cells with expression in the Goto Kakizaki rat being significantly reduced. We also observe significant differences in the glucose-induced Ca2+-signaling in the Goto Kakizaki rat. Our results suggest that chronic hyperglycemia in the Goto Kakizaki rat reduces expression of TRPM5 and leads to pancreatic ß-cell dysfunction thereby contributing to the progression of type 2 diabetes.
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    Undernutrition, brain composition and behavior in rats
    ([Honolulu], 1968) Guthrie, Helen Andrews
    The purpose of the present study was two-fold. The first was to assess the effect of varying periods of undernutrition from birth through nine weeks of age, followed by nutritional rehabilitation with an adequate diet, on growth, brain size and composition and learning capacity in mature male rats; the second was to determine if there is a critical period in the development of the brain after which it is refractory to nutritional rehabilitation. Undernutrition was achieved by feeding litters of 16 pups on a dam fed an 8 per cent casein diet and feeding a diet of 3 per cent casein at weaning. Control rats were fed in litters of eight by a dam on the same 18 per cent casein diet to which the pups were weaned at 21 days. Undernourished pups were changed to an adequate diet at three, five, seven or nine weeks of age. Rats were maintained in an environment controlled for temperature, light and stimulation. Beginning at 16 weeks the mature rats were given a series of behavioral tests--exploratory activity in a novel situation, emotionality, activity level, neuromuscular coordination and learning in an avoidance learning situation. At 19 weeks the animals were killed by ether anesthesia. The weighed brains were analyzed for DNA, RNA, cholesterol and phospholipid phosphorus content. No differences were found in learning capacity as assessed by avoidance conditioning, or in neuromuscular coordination or emotionality. The undernourished animals were significantly (p < .01) more active than the adequately nourished controls whereas the larger, well nourished animals reared on their hind legs more frequently in an exploratory situation. Data on brain composition showed that the animals undernourished during suckling had smaller brains, with fewer cells as measured by DNA content (p < .01) than those adequately nourished from birth. An adequate diet introduced at weaning did not stimulate cell proliferation. Those animals deprived five or more weeks had significantly less total brain cholesterol than those rehabilitated after deprivation during sucking only (p < .01). This confirms other findings and shows that the critical period for cholesterol deposition indicative of myelin formation is in the first five weeks of life. There were no differences in the phospholipid phosphorus content of brains of deprived and adequately nourished rats. RNA values did not differ significantly among groups but were correlated r = 0.90 with DNA values. RNA: DNA ratios were approximately 1.0 for all groups. On the basis of weight there were no differences in the chemical composition of the brains of deprived and well nourished control rats. The animals with smaller brains learned to avoid shock in a shuttle box equally as well as well-nourished controls with larger brains of similar chemical composition and were significantly (p < .01) more active.
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    Water content of expired air in man
    ([Honolulu], 1967) Buck, Alan Charles
    Five determinants of the water content of air expired by man were examined and attempts made to quantify each determinant. Each of the four determinants: ambient temperature, ambient humidity, tidal volume and respiratory frequency was examined at both sea level and altitude. The data collected from 14 men, at 7 ambient temperatures (-35° to +35° C), and 5 minute ventilation rates (which formed a continuum from 4 to 80 L STPD/min.), were corrected and statistically analyzed by computer. The results, presented in graphic, tabular and algebraic form, permit calculation of expired water or net water loss through the respiratory tract in man with corrections for minute volume, ambient temperature, gas density and ambient humidity. An attempt is made to explain the results presented using the notations of thermodynamics. It is assumed that the human respiratory tract is an efficient but limited counter-current heat and mass (water) exchange system. As such, the caloric requirements for equilibrating the respired air to 37°C and approximately 100% relative humidity are contingent upon the five determinants listed. The impact of a change in gas density is completely described in theory, listing changes in molar volume, heat capacity and gas flow characteristics, and how these changes might affect the heat and mass transfer between the respiratory mucosa and the respired air. Several semi-quantitative tables are given which permit a rough estimation of hourly or daily water loss from the respiratory tract for man under various conditions of ambient temperature and oxygen consumption.