Intravenous injection of substance P (SP) increases renal nerve firing and heart rate in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) by stimulating sympathetic ganglia. Blood pressure is increased in SHRs but lowered in WKYs. This study assesses the role of neurokinin-1 (NK1) receptors in mediating the ganglion actions of SP. Rats for functional studies were anesthetized and then treated with chlorisondamine. Renal nerve, blood pressure, and heart rate responses to intravenous injection of the NK1 receptor agonist GR-73632 were similar but less than those to equimolar doses of SP in SHRs. GR-73632 only slightly increased renal nerve firing and heart rate and lowered blood pressure in WKYs. The NK1 receptor antagonist GR-82334 (200 nmol/kg iv) blocked the ganglionic actions of GR-73632 and the pressor response to SP in SHRs. It reduced the renal nerve and heart rate responses by 52 and 35%. This suggests that the pressor response to SP is mediated by ganglionic NK1 receptors and that NK1 receptors also have a prominent role in mediating the renal nerve and heart rate responses to SP. Quantitative autoradiography showed that NK1 receptors are more abundant in the superior cervical ganglia of SHRs. RT-PCR showed increased abundance of NK1 receptor mRNA in SHRs as well. These observations suggest that the greater ganglionic stimulation caused by SP in SHRs is due to upregulation of NK1 receptors.

Indiana University-Purdue University Indianapolis (IUPUI) / Fluoridation of community water supplies for the purpose of preventing dental caries remains one of the top 10 public health interventions of the last century. However, exposure (ingestion) of greater than optimal amounts of fluoride from a variety of sources has led to an increase in the prevalence of dental fluorosis. We propose that dental fluorosis represents a complex condition caused by environmental and genetic factors. Purpose: To assess the role of genetics in the pathogenesis of dental fluorosis using genetically separate inbred strains of mice. Methods: Twelve genealogically disparate strains of mice were treated with 0 ppm, 25 ppm, and 50 ppm of fluoride in their drinking water. Each mouse was given weekly dental fluorosis evaluations. After 60 days of treatment, femurs were collected for fluoride analysis. Mandibular incisors were isolated for quantitative light induced fluorescence (QLF) studies and fluoride analysis. Digital and 35 mm images were taken of all mouse incisors in order to apply and compare the Dean's Index and the modified Thylstrup and Fejerskov Index (TFI), both indices of dental fluorosis. Skeletal radiographs were taken on the euthanized mice and later examined for extra skeletal calcifications and other gross bony deformities. Results: Differences in dental fluorosis susceptibility/resistance were identified between the strains, ranging from mild, moderate, to severe dental fluorosis. Furthermore, we found clustering of strains into distinct phenotypic groups. The A/J mouse strain was highly susceptible, with a rapid onset and severe development of dental fluorosis compared with the other strains tested. The 129P3/J mouse strain was least affected with negligible dental fluorosis. From the skeletal radiographs, no gross skeletal lesions or evidence of bone dysplasia were noted. Similar body burden of fluoride, as judged from analysis of mineralized tissues, was seen in all strains despite differences in their predispositions to develop dental fluorosis. Both the Dean's and TF indices are useful for classifying the stage or severity of fluorosis in mice, and there are advantages to the use of digital images over conventional 35 mm slide images. Both indices correlate well with the amount of fluoride exposure during amelogenesis; however, these indices are not promising indicators of fluoride burden during amelogenesis. Conclusions: QLF proved to be an innovative and useful tool for the quantification of dental fluorosis. Furthermore, these observations support the role of a genetic component in the pathogenesis of fluorosis.

京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第24809号 / 人健博第115号 / 新制||人健||8(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 中尾 恵, 教授 岡 昌吾, 教授 浅野 雅秀 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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Indiana University-Purdue University Indianapolis (IUPUI) / External apical root resorption (EARR) is a common complication of orthodontic treatment. Genetic factors account for approximately 50% of the variation in EARR. Data have indicated variation in histological root resorption associated with orthodontic force (RRAOF) among different inbred strains of mice. Differences in expression of RANKL and OPG were investigated in two strains of mice with different susceptibility to RRAOF using irnmunohistochemistry. Increased localization of RANKL was detected in the tissues surrounding the root of the susceptible strain compared to the resistant strain and the controls. In contrast, increased localization of OPG was found in the tissues surrounding the roots in the resistant A/J strain compared to the susceptible DBA/2J strain. We conclude that differences in the expression of these key bone resorption mediators play a role in determining RRAOF susceptibility. Changes in serum TRAP 5b level in response to orthodontic force were investigated among female A/J, DBA/2J and BALB/cJ mice. The three strains differed in their TRAP positive cell numbers as well as their serum TRAP 5b level at baseline and when treated. A significant increase in the serum TRAP 5b level with treatment was only detected in the RRAOF susceptible DBA/2J strain, and not in RRAOF resistant strains. Our analysis indicates that differences in osteoclast/odontoclast activity play a role in susceptibility to RRAOF that is genetically determined. Serum TRAP 5b levels have a potential role in screening for individuals with greater susceptibility to root resorption. RRAOF was determined for male and female mice of the A/J, DBA/2J and BALB/cJ strains, as well as A/J x DBA/2J and A/J x BALB/cJ crosses. Sex differences were observed among the BALB/cJ strain only, with females more resistant to RRAOF when compared to males. Fis from the A/J x BALB/cJ cross were resistant suggesting that the A/J have dominant resistance alleles, while Fis from the A/J x DBA/2J cross had RRAOF intermediate between their parental A/J and DBA/2J mice, suggesting a polygenic trait. We concluded that the mode of inheritance of RRAOF in mice was polygenic in nature.

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Optimal plant populations are critical in achieving high rice yields. The purpose of this research was to investigate yield penalties associated with inadequate, non-uniform plant populations for modern rice cultivars. Research was conducted at the Delta Research and Extension Center in Stoneville, MS, in 2019, 2020 and 2021. In one study, inbred, herbicide-resistant ‘CL153’ was drill-seeded at 73-18 kg ha-1 after being mixed with inbred, herbicide-susceptible ‘Rex’ at 0-55 kg ha-1. Likewise, hybrid, herbicide-resistant cultivar ‘CL XL7521’ was seeded at 29-8 kg ha-1 mixed with hybrid, herbicide-susceptible ‘XP753’ at 0-21 kg ha-1. At the two- to three- leaf growth stage, imazamox was applied to eliminate ‘Rex’ and ‘XP753’ in their respective studies to achieve the target plant population (TPP). Results indicate that when plant populations are reduced up to 30% in both inbred and hybrid cultivars, grain yields should be comparable if not greater than an adequate, uniform plant population.

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The generation of recombinant antibodies (Abs) using phage display is a proven method to obtain a large variety of Abs that bind with high affinity to a given antigen. Traditionally, the generation of single-chain Abs depends on the use of recombinant proteins in several stages of the procedure. This can be a problem, especially in the case of cell-surface receptors, because Abs generated and selected against recombinant proteins may not bind the same protein expressed on a cell surface in its native form and because the expression of some receptors as recombinant proteins is problematic. To overcome these difficulties, we developed a strategy to generate single-chain Abs that does not require the use of recombinant protein at any stage of the procedure. In this strategy, stably transfected cells are used for the immunization of mice, measuring Ab responses to immunization, panning the phage library, high-throughput screening of arrayed phage clones, and characterization of recombinant single-chain variable regions. This strategy was used to generate a panel of single-chain Abs specific for the innate immunity receptor Toll-like receptor 2. Once generated, individual single-chain variable regions were subcloned into an expression vector allowing the production of recombinant Abs in insect cells, thus avoiding the contamination of recombinant Abs with microbial products. This cell-based system efficiently generates Abs that bind to native molecules on the cell surface, bypasses the requirement of recombinant protein production, and avoids risks of microbial component contamination. / Dissertation