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京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20271号 / 医博第4230号 / 新制||医||1021(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 富樫 かおり, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Communication by voice is foundational in our society and many rely on their voices for their occupations. Voice disorders affect a significant number of individuals each year, and diagnosis and treatment improvements are therefore sought via advancements in voice research. Contained in this thesis is a description of work intended to contribute to vocal fold research by using synthetic, self-oscillating vocal fold replicas to study the impact of replica vibration on perfusion fluid flow through the replica. Methods for manufacturing vocal fold replicas containing imbedded channels allowing for fluid perfusion are discussed. Experimental procedures developed for delivering perfusion fluid to the imbedded channel at a constant pressure during replica vibration are described. Methods for measuring perfusion parameters of perfusion fluid pressure, imbedded channel diameter, flow rate, and vibration parameters (subglottal pressure, frequency, amplitude, channel length, and glottal width) are detailed. Experiments performed using both stationary and vibrating vocal fold replicas are presented. Correlations between perfusion pressure and channel diameter are discussed. Vibration parameters were correlated to perfusion flow parameters and it is shown that perfusion flow rate through the channels decreased significantly with model vibration. Potential mechanisms for changes in perfusion flow resistance with vibration are discussed and analyzed. Output of a theoretical model, developed to incorporate some of the possible flow resistance mechanisms, was compared to vibrating replica experimental data.

Glioblastoma Multiforme (GBM) is the most common brain cancer and one of the most fatal forms of cancer overall. The average survival time is 10-14 months, and less than 10% of patients survive more than 5 years after diagnosis. It is characterized by extreme vasculature, chemo/radioresistance, and invasiveness into the normal brain. The current standard of care, which includes surgical removal of tumor, radiation, and the chemotherapeutic agent temozolomide, initially stunt tumor growth. Nevertheless, the tumor invariably rebounds and the patient succumbs to the disease. Therefore, there is an urgent need to develop new therapies for this devastating disease. YKL-40 is one of the most over-expressed proteins by GBM cells, and is elevated in the serum of patients with GBM. YKL-40 is implicated in a host of inflammatory diseases and has been shown to play a major role in the maturation of some cells of the immune system, especially macrophages. Thus, it has been suggested that YKL-40 may act as a prognostic biomarker for cancer and inflammatory disease. However, little is known about the role of YKL-40 in relation to cancer development and progression, and more work needs to be done to validate it as a biomarker or as a therapeutic target. It was the goal of the work described herein to uncover some of the key molecular mechanisms of GBM development and progression in the hopes of offering new therapeutic targets. Using a wide variety of in vitro and in vivo techniques, the role of a secreted glycoprotein YKL-40 in GBM was probed. It was demonstrated that YKL-40 enhanced angiogenesis, radioresistance, and progression of GBM cells. Moreover, inhibition of YKL-40 in mouse models markedly arrested tumor growth and vascularization, lending support to the idea of YKL-40 as a therapeutic target. Finally, YKL-40 drove GBM cells into a mesenchymal phenotype, where the tumor cells act as mural-like cells, supporting tumor vasculature networks. Hopefully, the results from these studies will offer the rationale to develop drugs against YKL-40 and potentially extend the lives of patients with this terrible disease.

Purpose: The purpose of this study was to investigate the role of the vasculature and immune system in models of glaucoma. Vascular changes have been implicated in glaucoma. As well there is mounting evidence that the immune system plays a role in the disease. It is my hypothesis that the vasculature and immune system play a role in the retinal response to injury in models of glaucoma. Methods: Immunohistochemistry, in vivo retinal imaging (Bright field, fluorescent, optical coherence tomography), Slit2 injections and Evan’s blue labeling were used to investigate vascular and immune changes associated with retinal ganglion cell death after optic nerve crush up to 28 days after injury. Histology, immunohistochemistry, and intravascular labeling were utilized to investigate the role of the vascular degeneration and the systemic immune response to elevated intraocular pressure in 8-16 week old AP-2β Neural Crest Cell Knockout (AP-2β NCC KO) mice. Results: The vascular and immune responses to optic nerve crush were not found to play a significant role in the response to retinal ganglion cell death. Conversely the role of vascular degeneration and immune cell recruitment to the retinas of AP-2β NCC KO mice demonstrated that these factors played a significant role in the retinal response to injury. Conclusion: The vasculature and immune system play a varied role in the response to retinal injury and neurodegeneration depending on the model being studied. The vascular and immune changes were of minimal significance in acute optic nerve crush injury. On the other hand, the chronic injury associated with elevated intraocular pressure in AP-2β NCC KO mice was associated with significant vascular degeneration and systemic immune cell infiltration. / Thesis / Doctor of Philosophy (PhD)

The vascular system is critical infrastructure that transports oxygen and nutrients around the body, and dynamically adapts its function to an array of environmental changes. To fulfil the demands of diverse organs, each with unique functions and requirements, the vascular system displays vast regional heterogeneity as well as specialized cell types. Our understanding of the heterogeneity of vascular cells and the molecular mechanisms that regulate their function is beginning to benefit greatly from the rapid development of single cell technologies. Recent studies have started to analyze and map vascular beds in a range of organs in healthy and diseased states at single cell resolution. The current review focuses on recent biological insights on the vascular system garnered from single cell analyses. We cover the themes of vascular heterogeneity, phenotypic plasticity of vascular cells in pathologies such as atherosclerosis and cardiovascular disease, as well as the contribution of defective microvasculature to the development of neurodegenerative disorders such as Alzheimer’s disease. Further adaptation of single cell technologies to study the vascular system will be pivotal in uncovering the mechanisms that drive the array of diseases underpinned by vascular dysfunction.

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<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>Pre-clinical imaging has provided pulmonary researchers with a number of valuable tools for studying both the lung and lung disease. A greater understanding of the structure/function relationships within the rodent lung would help to bridge the gap between functional images of the lung and its underlying anatomy.</p> <p>The objectives of this work were to visualize and measure the components of rodent lung anatomy. Contrast-enhanced microCT images were used to visualize the airways and major blood vessels from both the Sprague-Dawley rat and the BALB/c mouse. These observations and measurements were used in the development of a pulmonary lung model containing both the conducting airways and blood vessels. The model can be applied to unenhanced images of the rodent lung to facilitate the regionalization of functional imaging data (SPECT/PET). The model has been used to simulate bronchoconstriction and deposition patterns of inhaled particles. Extensive validation revealed that the model was unable to fully reproduce the rodent lung and that further refinement is necessary.</p> <p>The finer structure of the rodent lung, which could not be resolved using our microCT system, was measured using histological sections of the rodent lung. Software was developed and validated to automatically quantify the increases in airspace size that are associated with several respiratory conditions.</p> <p>Together, this work sheds light on the underlying anatomy of the rodent lung that is present in both anatomical and functional images. The knowledge will help researchers to understand some of the structural changes that are occurring with the development of lung disease.</p> / Doctor of Philosophy (PhD)