Abstract In homeothermic birds and mammals, several thermoregulatory adaptations have evolved for surviving in unstable, food-restricted conditions. This study focuses on two adaptive mechanisms in pigeons (Columba livia) and quails (Coturnix coturnix japonica): hypothermia and the adaptive use obligatory heat production connected with feeding and digestion. The plasticity of the hypothermic response in fed and fasted birds and birds with restricted feeding was studied in laboratory and outdoor winter conditions. The other objective was to study adaptive timing of digestion, and substitution of facultative thermogenesis by obligatory heat production in cold and at thermoneutrality. The results showed that fasting has a strong influence on the level of nocturnal hypothermia in laboratory conditions: hypothermia becomes progressively deeper when fasting continues. In outdoor conditions, ambient temperature and predation risk modulated the daily body temperature (Tb) pattern of fasting pigeons. In very cold conditions, diurnal Tb of fasted birds also dropped below the normal level of the active phase. Predation risk prevented diurnal hypothermia but also attenuated the depth of nocturnal hypothermia in fasting pigeons. This study provides the first empirical effects of predation risk on hypothermia in starving birds. The study suggests that the presence of crop in pigeons allows adaptive timing of digestion. At thermoneutrality, peak digestion appeared late in the dark phase in birds with fed in the morning. Because the Tb of the birds increases to diurnal levels late in the dark phase, this obligatory heat from digestion can be used to aid re-warming by such timing. On other hand, the results of this study were partly opposite to the classical model of thermoregulatory substitution. In line with the classical model, a postprandial increase in metabolic rate (heat increment of feeding, HIF) was seen at thermoneutrality but not in cold. However, electromyographic measurements showed that there was no postprandial decrease in the intensity of shivering in the fed birds in cold. This indicates that true thermoregulatory substitution may be less common than assumed and suggests a role for facultative thermogenesis in HIF.

La radiothérapie thoracique peut induire le développement de pneumopathies aiguës et de fibroses. La dysfonction du système vasculaire participe au développement de lésions radiques. Dans l'intestin, un KO endothélial de PAI-1 protège les souris de la fibrose radique. Le premier objectif de ce projet est d'explorer le rôle de PAI-1 dans l'apparition de la fibrose radique pulmonaire. L'irradiation thoracique de souris à 17 Gy altère sévèrement le parenchyme pulmonaire et l'analyse histologique révèle que l'invalidation de PAI-1 aggrave les lésions à 2 et 13 semaines. Cette invalidation ne protège donc pas les animaux des dommages radiques pulmonaires. L'organisation en parallèle du poumon permet d'envisager une tolérance à de fortes doses par fraction sur des petits volumes. Des irradiations en conditions stéréotaxiques ont donc été réalisées chez la souris. Les analyses histologiques montrent une déstructuration alvéolaire et un fort infiltrat inflammatoire au niveau de la zone cible. Un œdème est observable dans l'ensemble du poumon ipsilatéral deux semaines après irradiation. Le poumon ipsilatéral est également affecté par des altérations de structure, tel un épaississement des septa alvéolaires. Ces bouleversements se traduisent également au niveau transcriptomique. A la vue de l'ensemble de ces altérations, un test à l'effort a été réalisé pour évaluer l'impact potentiel sur la fonction pulmonaire. Les résultats mettent en évidence une diminution des performances des animaux. Les analyses sont à approfondir mais elles démontrent l'importance de s'intéresser aux tissus sains situés hors du volume cible mais recevant des fractions variables de la dose délivrée. / Radiation-induced endothelial dysfunction is known to participate to the development of normal tissue damage. PAI- is implicated in the phenotypic changes of irradiated endothelial cells and KOendo mice are protected from radiation damage to the gut. Whole thorax of PAI-1 KOendo and floxed mice were exposed to 17 Gy. Histological analyzes showed that PAI-1 KOendo induces a worsening of injuries at 2 and 13 weeks. Consequently, contrary to the gut no protection from radiation-induced lung damage is observed in PAI-1 KOendo mice. Our second aim was to study the effects of a single high dose stereotactic irradiation on pulmonary tissues. Histological analyzes and scanner imaging show important injuries on the targeted volume. An ipsilateral edema can also be observed 2 weeks after irradiation. Ipsilateral lung is moreover importantly damaged. A thickening of alveolar septa is notably observable. A transcriptomic analysis show important similarities between tissues from the ipsilateral lung and the focal lesion. As really highly damages have been observed in both scanner and histological analyzes, we decided to perform forced physical activity test on treadmill. A drastic decrease of maximal distance traveled has been observed from two weeks. These experiments highlighted a deficiency in respiratory function and all of these results show the importance of non-targeted irradiated pulmonary volume in the development of radiation-induced fibrosis. Effect of an endothelium-specific deletion of HIF-1α has been investigated in this model of stereotactic irradiation. Only few differences have been observed between KOendo and control mice. Experiments are still ongoing.

Cold adaptation and her effects has been known for many decates. Positive or negative impact depends especially on its length and strength. The lower temperature can very often cause the stress for organism. On the other hand in expreriment with long-term adapatation were found positive consequences on cardiovascular system. We found the lack of studies devoted to the energy metabolism and apoptosis in heart tissue during long-term cold adaptation. In this work we used a model with milder conditions of the adaptation (10žC±1), so there wouldn't be damage of the experimental animals. We compared the resuls betwen control, cold and regressive group of rats. In this expreriment we used methods of electrophoresis and Western blot. The target of the work was found if we can find any differences betwen chosen HIF targeted genes. The next goal was to detect the differences betwen chosen pro-apoptotic and anti-apoptotic markers. Keywords: cold adaptation, heart, energetic metabolism, HIF, apoptosis

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1β production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1β expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18883号 / 医博第3994号 / 新制||医||1009(附属図書館) / 31834 / 京都大学大学院医学研究科医学専攻 / (主査)教授 岩井 一宏, 教授 野田 亮, 教授 藤田 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Stroke is the world's leading cause of adult disability, caused by lack of oxygen and nutrients to the brain due to a blood clot in a major artery. This leads to ischemic damage of neuronal cells that leads to paralysis, motor, and speech deficits. While most stroke therapies aim at removing or reducing the blood clots in the brain, few treatments target cell damage. Neuroglobin (NGB) is a protein in the brain that is able to aid in neuroprotection following oxidative stress. Hypoxia-Inducible Factor-1 (HIF-1) is a transcription factor that serves as a marker for cell recovery after hypoxia or low oxygen levels. Exosomes are microscopic extracellular vesicles that can help deliver proteins across the blood-brain barrier. This thesis focuses on finding a correlation between exosomal-delivered neuroglobin to ischemic cells and the regulation of HIF-1 in order to develop an innovative treatment using exosomes. The specific aims of this thesis are as follows: Aim 1: Package NGB in exosomes of healthy cell The XPAK-NGB plasmid will be used to transfect NGB DNA into wild-type human embryonic kidney (HEK-293 cell line) cells. Exosomes will be harvested from the spent media. The exosomes will be analyzed to ensure that the protein is packaged inside the exosomes. Aim 2: Determine the limit of hypoxic conditions and effects of NGB on damaged cells A literature review will be performed to determine the ideal concentration of H2O2 for the survival of neuronal cells. This will include the composition of hypoxia as well as the length of time that cells can be exposed to and remain viable. Aim 3: Correlate NGB concentration and HIF-1 concentration Another literature review will determine the specific markers of NGB and HIF-1.

Indiana University-Purdue University Indianapolis (IUPUI) / High choline uptake and increased choline kinase activity have been reported in many cancers. This has motivated the use of choline as a biomarker for tumor imaging. Tumors in general are heterogeneous in nature with respect to oxygen tension. There are regions of hypoxia and normoxia that are expected to have different metabolism but regulation of choline metabolism under hypoxia is poorly understood. It is important to clarify the status of choline metabolism in hypoxic microenvironment as it will have an impact on potential of choline as a cancer biomarker. The primary goal was to determine the status of choline phosphorylation in hypoxic cancer cells and its effect on uptake of choline. This was examined by tracer studies in cancer cells exposed to hypoxia. It was observed that hypoxia universally inhibits choline uptake /phosphorylation in cancer cells. Decreased choline phosphorylation resulted in transient uptake of choline radiotracers in cultured cancer cells and 9L tumors suggesting potential problem in using choline as a biomarker for cancers in hypoxic microenvironment. To investigate the mechanism behind decrease in choline phosphorylation, steady state levels of choline metabolites were measured and choline kinase catalyzed choline phosphorylation step was found to be rate-limiting in PC-3 cells. This suggested that modulation in choline kinase levels can alter choline metabolism in hypoxic cancer cells. Expression and activity assays for choline kinase revealed that choline kinase expression is down-regulated in hypoxia. This regulation involved transcriptional level mediation by HIF1 at the conserved HRE7 site in choline kinase promoter. To further understand the importance of down-regulation of choline kinase in hypoxia, stable prostate cancer cell lines over-expressing choline kinase were generated. Effect of over-expression of choline kinase in hypoxia was evaluated in terms of malignant phenotypes like proliferation rate, anchorage independent growth and invasion potential. Both over-expression of choline kinase and hypoxia had a pronounced effect on malignant phenotypes of prostate cancer cells. Further study showed that increased choline kinase activity and hypoxic tumor microenvironment are important for progression of early-stage, androgen-dependent LNCaP prostate cancer cells but confer little survival advantage in undifferentiated, androgen-independent PC-3 prostate cancer cells.

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