京都大学 / 新制・論文博士 / 博士(医学) / 乙第13573号 / 論医博第2299号 / 新制||医||1069(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 妹尾 浩, 教授 藤田 恭之, 教授 伊藤 貴浩 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Microbiota-released extracellular vesicles (MEVs) have emerged as key players in intercellular signaling in host-microbiome communications. However, their role in gut-brain axis signaling has been poorly investigated. Here, we performed deep multi-omics profiling of MEVs generated ex-vivo and from stool samples to gain insight into their role in gut-brain-axis signaling. Metabolomics unveiled a wide array of metabolites embedded in MEVs, including many neurotransmitter-related compounds such as arachidonyl-dopamine (NADA), gabapentin, glutamate, and N-acylethanolamines. To test the biodistribution of MEVs from the gut to other parts of the body, Caco-2, RIN-14B, and hCMEC/D3 cells showed the capacity to internalize labeled MEVs through an endocytic mechanism. Additionally, MEVs exhibited dose-dependent paracellular transport through Caco-2 intestinal cells and hCMEC/D3 brain endothelial cells. Overall, our results revealed the capabilities of MEVs to cross the intestinal and blood-brain barriers to delivering their cargo to distant parts of the body.

Levels of circulating large extracellular vesicles (L-EVs) are increased in individuals with type 1 diabetes mellitus (T1DM) and associated with increased cardiovascular risk. T1DM in pregnancy induces vascular injury leading to adverse maternal and neonatal outcomes. Conversely, exercise has been shown to improve cardiovascular and metabolic health in pregnancy and may represent a non-pharmacological approach to improving pregnancy outcomes. Assessment of vascular health may aid in the identification of individuals at risk of complications and allow for intervention with strategies to improve the maternal vasculature. Unfortunately, there is a paucity of strategies for assessing vascular health in pregnant women. L-EVs are membrane-encapsulated particles released from stressed/injured cells. They are emerging biomarkers of vascular health. The purpose of this thesis was to assess the impact of T1DM and pregnancy on L-EV levels and protein composition, the relationship between L-EVs and pregnancy outcomes and the effect of exercise on L-EV levels. In aim #1, I observed that high levels of L-EVs are predictive of adverse pregnancy outcomes. In aim # 2, I examined the protein composition of circulating L-EVs in hypertensive, diabetic and healthy mice models. Diabetes-enriched proteins were involved in inflammation, SNARE signaling and NAD+ biogenesis. The changes were found in L-EV protein content were consistent with proteins associated with inflammation, cytoskeletal organization, and angiogenesis. Finally, in aim #3, I examined the changes in plasma L-EVs after an acute bout of moderate-intensity aerobic exercise in healthy pregnant and non-pregnant women. I observed that circulating L-EVs significantly decreased after the acute exercise only in non-pregnant individuals. Taken together, my thesis work advances knowledge on L-EVs in T1DM, pregnancy, and hypertension and sets the stage for future work on L-EVs as predictive biomarkers, for molecular profiling, and for monitoring of vascular health interventions in pregnancy.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24840号 / 医博第5008号 / 新制||医||1068(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 藤田, 恭之, 教授 松田, 道行, 教授 柳田, 素子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24993号 / 医博第5027号 / 新制||医||1069(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 滝田 順子, 教授 岩田 想, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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