慶應義塾研究者情報データベース

経歴 【 表示 ／ 非表示 】

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• 2002年10月

  -

  2015年03月

  慶應義塾大学, 医学部小児科, 研究員

• 2010年04月

  -

  2015年03月

  東京家政学院大学, 現代生活学部健康栄養学科, 准教授

• 2015年04月

  -

  継続中

  慶應義塾大学, 保健管理センタ―, 専任講師

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• 1988年04月

  -

  1994年03月

  慶應義塾大学, 医学部

  大学, 卒業

学位 【 表示 ／ 非表示 】

学位 【 表示 ／ 非表示 】

• 博士(医学), 慶應義塾大学, 論文, 2005年12月

免許・資格 【 表示 ／ 非表示 】

免許・資格 【 表示 ／ 非表示 】

• 医師免許, 1994年05月

• 日本小児科学会小児科専門医, 1998年05月

• 日本小児循環器学会小児循環器専門医, 2015年

研究分野 【 表示 ／ 非表示 】

研究分野 【 表示 ／ 非表示 】

• ライフサイエンス / 胎児医学、小児成育学

• ライフサイエンス / 発生生物学

• ライフサイエンス / 細胞生物学

研究キーワード 【 表示 ／ 非表示 】

研究キーワード 【 表示 ／ 非表示 】

• Cardiovascular development

• Calcium signaling

研究テーマ 【 表示 ／ 非表示 】

研究テーマ 【 表示 ／ 非表示 】

• Calcium signaling in physiology and pathology, 

  1998年07月

  -

  継続中

• 心血管疾患の発生と先天性心血管疾患の発症機序の解明, 

  2002年10月

  -

  継続中

著書 【 表示 ／ 非表示 】

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• Roles of Tbx4 in the lung mesenchyme for airway and vascular development

  Uchida K., Yoshida Y., Kodo K., Yamagishi H., Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension, 2020年01月

  　概要を見る

  The T-box family genes are evolutionarily conserved transcription factors. In particular, Tbx4 and Tbx5 are closely conserved and play crucial roles in development and organogenesis. Tbx4 is essential for hindlimb and allantoic vessel formation [1]. It is also highly expressed in the lung mesenchyme (Fig. 8.1), initially expressed at embryonic day (E) 9.25 and later expressed throughout murine embryogenesis [2].

• Roles of stem cell antigen-1 in the pulmonary endothelium

  Maeda J., Uchida K., Kodo K., Yamagishi H., Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension, 2020年01月

  　概要を見る

  There is growing evidence that resident progenitor cell populations exist in murine lung tissues and differentiate into a mesenchymal cell lineage [1, 2]. Stem cell antigen-1 (Sca-1) is a cell surface glycoprotein, initially found in murine bone marrow-derived stem cell subtypes, such as hematopoietic stem cells. Some studies showed Sca-1 expression in the pulmonary vascular endothelium of adult murine lungs [3], while a subset of Sca-1-expressing cells formed vascular-like structures under specific conditions [1].

• Ca2+ signal through inositol trisphosphate receptors for cardiovascular development and pathophysiology of pulmonary arterial hypertension

  Shibata A., Uchida K., Mikoshiba K., Yamagishi H., Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension, 2020年01月

  　概要を見る

  Inositol triphosphate receptor (IP3R) is an intracellular Ca2+ release channel located on the membrane of the sarco/endoplasmic reticulum (SR/ER), a major intracellular storage site for Ca2+. There are three subtypes of IP3R the pathophysiology of many organs [1].

• A genetic analysis for patients with pulmonary arterial hypertension

  Yoshida Y., Uchida K., Kodo K., Furutani Y., Nakanishi T., Yamagishi H., Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension, 2020年01月

  　概要を見る

  Pulmonary arterial hypertension (PAH) is a lethal disease [1]. Although mutations in BMPR2 and other genes have been reported, the genetic causes in large numbers of patients, especially with sporadic PAH, remain unknown. In 2013, Kerstjens-Frederikse et al. first reported TBX4 mutations in patients with PAH [2]. TBX4 is an essential transcription factor for the development of the hindlimbs and lungs [3]. In European countries, the frequency of TBX4 mutation was reported as 2.4-4.1% in adult-onset PAH [2, 4] and as 7.5-30% in child-onset PAH [2, 5] (Fig. 27.1). However, its frequency in Asian patients with PAH has yet to be studied.

• A lacZ reporter transgenic mouse line revealing the development of pulmonary artery

  Ishizaki R., Uchida K., Shibata A., Tsuchihashi T., Maeda J., Mikoshiba K., Yamagishi H., Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension, 2020年01月

  　概要を見る

  Pulmonary vasculature in mice develops through two main mechanisms, namely angiogenesis and vasculogenesis. At embryonic day (E) 9.5, vascular endothelial marker Tie2-driven LacZ expression in whole-mount transgenic lungs showed continuity between the primitive lung vasculature and the aortic sac [1]. Scanning electron microscopic study of vascular casts and graphic reconstruction in the 32- and 34-somite (E10) embryos demonstrated that the primordium of the pulmonary artery (PA) arose from the proximal portion of the sixth pharyngeal arch artery and ran straight in the caudal direction [2]. At E10.5, though the afferent vessels were not yet defined as vascular tubes, they resembled two plexiform networks that coalesce alongside the trachea. From these observations, “distal angiogenesis” was proposed as a model for the pulmonary vascular morphogenesis where PAs arise from the pharyngeal arch artery and elongate into the lung buds [1]. Another study provided evidence to support vasculogenesis as the mechanism of both proximal and distal vessel formation during the development of murine lungs [3]. Detailed analysis using Mercox vascular casts revealed that vasculogenesis occurred peripherally in the lungs to form isolated blood islands and that angiogenesis centrally forms the axial and lateral arteries and veins. The fusion and coalescence of these central and peripheral systems lead to the development of the pulmonary circuit [4]. The earliest connection between the peripheral and central spaces was identified between E13 and E14.

論文 【 表示 ／ 非表示 】

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• Pediatric blood pressure category predicts longitudinal blood pressure change in adolescence and early adulthood

  Azegami T., Uchida K., Sato Y., Murai-Takeda A., Inokuchi M., Itoh H., Mori M.

  Pediatric Research （Pediatric Research)  2023年

  ISSN  00313998

  　概要を見る

  Background: Patterns of blood pressure (BP) change from early adolescence to young adulthood have not been well-described. The objective of this study was to examine the predictive value of pediatric BP classification on BP change and identify subpopulations with large BP increases during adolescence and early adulthood. Methods: Baseline data were obtained from medical checkups of Japanese adolescents aged 12–13 years in 2009 or 2010 and subsequent BP values were followed for a 9-year period. Mixed-effects models were used to estimate the effects of baseline factors on subsequent BP changes. Results: Hypertensive and elevated BP group consistently had higher BP values than normal BP group throughout the observation period. Multivariate mixed-effects model analyses revealed group-by-time interactions between systolic BP change and BP category in males and uric acid category in females, and between diastolic BP change and white blood cell count in males and obesity and high-density lipoprotein cholesterol in females; however, these factors had limited effects on the rate of BP increase, indicating that they are not suitable as clinical predictors of BP increase. Conclusions: Pediatric BP category predicted BP values, but there was no factor that identified subpopulations with large BP increases in adolescence and early adulthood. Impact: Blood pressure category in the American Academy of Pediatrics clinical practice guideline at age 12–13 years predicted subsequent blood pressure values during adolescence and early adulthood.No baseline factor that identified a subpopulation with large increase in blood pressure during adolescence and early adulthood in clinical practice was found.Our study contributes to the existing literature by demonstrating the usefulness of the American Academy of Pediatrics clinical practice guideline for blood pressure classification in a Japanese population.

  • Access to Document (DOI)

• A genetic and developmental biological approach for a family with complex congenital heart diseases—evidence of digenic inheritance

  Yoshida Y., Uchida K., Kodo K., Ishizaki-Asami R., Maeda J., Katsumata Y., Yuasa S., Fukuda K., Kosaki K., Watanabe Y., Nakagawa O., Yamagishi H.

  Frontiers in Cardiovascular Medicine （Frontiers in Cardiovascular Medicine)  10 2023年

  　概要を見る

  Objective: Congenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study was to elucidate the multi-genetic origin and pathogenesis of an intriguing familial case with complex CHD. Methods: We performed an original trio-based gene panel analysis using NGS of the family, including two siblings with CHD of single ventricular phenotype, and their unaffected parents. The pathogenicity of the detected rare variants was investigated in silico, and the functional effects of the variants were confirmed in vitro using luciferase assays. The combinatorial effect of gene alterations of the putative responsible genes was tested in vivo using genetically engineered mutant mice. Results: NGS-based gene panel analyses revealed two heterozygous rare variants in NODAL and in TBX20 common to the siblings and to just one of parents. Both variants were suspected pathogenic in silico, and decreased transcriptional activities of downstream signaling pathways were observed in vitro. The analyses of Nodal and Tbx20 double mutant mice demonstrated that Nodal+/−Tbx20−/− embryos showed more severe defects than Nodal+/+Tbx20−/− embryos during early heart development. The expression of Pitx2, a known downstream target of Nodal, was downregulated in Tbx20−/− mutants. Conclusions: Two rare variants on NODAL and TBX20 genes detected in this family were considered to be loss-of-function mutations. Our results suggest that NODAL and TBX20 may be complementary for the cardiac development, and a combinatorial loss-of-function of NODAL and TBX20 could be implicated in digenic inherence as the etiology of complex CHD associated with single ventricle defects in this family.

  • Access to Document (DOI)

• Genetic and functional analyses of TBX4 reveal novel mechanisms underlying pulmonary arterial hypertension

  Yoshida Y., Uchida K., Kodo K., Shibata H., Furutani Y., Nakayama T., Sakai S., Nakanishi T., Takahashi T., Yamagishi H.

  Journal of Molecular and Cellular Cardiology （Journal of Molecular and Cellular Cardiology)  171   105 - 116 2022年10月

  ISSN  00222828

  　概要を見る

  Background: Pulmonary arterial hypertension (PAH) is a fatal disease, with approximately 10% of cases associated with genetic variants. Recent genetic studies have reported pathogenic variants in the TBX4 gene in patients with PAH, especially in patients with childhood-onset of the disease, but the pathogenesis of PAH caused by TBX4 variant has not been fully uncovered. Methods: We analysed the TBX4 gene in 75 Japanese patients with sporadic or familial PAH using a PCR-based bidirectional sequencing method. Detected variants were evaluated using in silico analyses as well as in vitro analyses including luciferase assay, immunocytochemistry and chromatin immunoprecipitation (ChIP) whether they have altered function. We also analysed the function of TBX4 using mouse embryonic lung explants with inhibition of Tbx4 expression. Results: Putative pathogenic variants were detected in three cases (4.0%). Our in vitro functional analyses revealed that TBX4 directly regulates the transcriptional activity of fibroblast growth factor 10 (FGF10), whereas the identified TBX4 variant proteins failed to activate the FGF10 gene because of disruption of nuclear localisation signal or poor DNA-binding affinity. Furthermore, ex vivo inhibition of Tbx4 resulted in insufficiency of lung morphogenesis along with specific downregulation of Tie2 and Kruppel-like factor 4 expression. Conclusion: Our results implicate variants in TBX4 as a genetic cause of PAH in a subset of the Japanese population. Variants in TBX4 may lead to PAH through insufficient lung morphogenesis by disrupting the TBX4-mediated direct regulation of FGF10 signalling and pulmonary vascular endothelial dysfunction involving PAH-related molecules.

  • Access to Document (DOI)

• Impact of school closure due to the coronavirus disease 2019 pandemic on body mass index in Japanese children: Retrospective longitudinal study

  Nagashima Y., Inokuchi M., Yasui Y., Uchida K., Tokumura M., Hasegawa T.

  Journal of Paediatrics and Child Health （Journal of Paediatrics and Child Health)  58 （ 10 ） 1841 - 1846 2022年10月

  ISSN  10344810

  　概要を見る

  Aim: During the coronavirus disease 2019 pandemic, the governments of many countries responded to high levels of infection with lockdowns. As a result, some children were reported to experience weight gain. The aim of the present study was to examine the impact of school closures on body mass index (BMI) in Japanese children. Methods: This was a retrospective study of students enrolled in the participating schools (6- to 11-year-old elementary school students and 12- to 14-year-old junior high school students) between 2015 and 2020. Using school health check-up data, annual changes in the BMI standard deviation score (ΔBMI-SDS) were calculated. We compared ΔBMI-SDS in 2019–2020 with the corresponding control years. Results: 19 565 children with complete data were included in the analysis. Median ΔBMI-SDS in 2019–2020 were 0.24–0.35 in elementary school boys, 0.10–0.13 in junior high school boys, −0.02 to 0.15 in elementary school girls and −0.14 to −0.10 in junior high school girls. In comparison with every control year, ΔBMI-SDS in 2019–2020 were significantly higher in elementary school boys (control years: −0.07 to 0.14) and junior high school boys (control years: −0.04 to 0.06), and significantly lower in junior high school girls (control years: −0.06 to 0.09). Conclusion: BMI-SDS increased significantly in elementary and junior high school boys, but decreased significantly in junior high school girls. The pandemic appears to have had an impact on Japanese children that was different from other countries.

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• Blood Pressure Tracking From Childhood to Adulthood

  Azegami T., Uchida K., Tokumura M., Mori M.

  Frontiers in Pediatrics （Frontiers in Pediatrics)  9 2021年11月

  　概要を見る

  Hypertension is the most common non-communicable disease among adults and is the most important modifiable risk factor for premature cardiovascular disease. The increasing worldwide burden of hypertension is a major global health issue. Early prevention with lifestyle modification or pharmaceutical treatment reduces the incidence of hypertension and the risk of subsequent cardiovascular disease. Therefore, identification of young persons at risk for hypertension has the obvious benefit of providing a chance for early intervention. Previous studies have demonstrated the positive association of elevated childhood blood pressure with hypertension in adulthood. Accumulated evidence also indicates the possibility that elevated pediatric blood pressure is associated with increased risk of future cardiovascular disease. In this article, we review the tracking of blood pressure from childhood to adulthood and emphasize the importance of pediatric blood pressure monitoring and control for predicting and preventing adult hypertension and cardiovascular disease.

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• 肺血管発生と肺高血圧症におけるTbx4の役割

  内田, 敬子

  科学研究費補助金研究成果報告書 2020年

• T-box遺伝子ファミリー機能解析による先天性心血管疾患発症機構の解明

  内田, 敬子

  科学研究費補助金研究成果報告書 2018年

• 肺血管幹細胞の同定と肺血管発生における分子機構の解明

  内田, 敬子

  科学研究費補助金研究成果報告書 2018年

• 肺動脈性高血圧症の進展を抑制する細胞内カルシウムシグナルの解明

  内田, 敬子

  科学研究費補助金研究成果報告書 2016年

• 動物モデルを用いた先天性心臓流出路異常の予防と新たな治療への基礎的研究

  内田, 敬子

  科学研究費補助金研究成果報告書 2015年

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競争的研究費の研究課題 【 表示 ／ 非表示 】

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• 肺動脈平滑筋標識マウスを用いた新規肺動脈成長促進因子の探索

  2020年04月

  -

  2023年03月

  文部科学省・日本学術振興会, 科学研究費助成事業, 内田 敬子, 基盤研究(C), 補助金,  研究代表者

• 肺血管発生と肺高血圧症におけるTbx4の役割

  2017年04月

  -

  2020年03月

  文部科学省・日本学術振興会, 科学研究費助成事業, 内田　敬子, 基盤研究(C), 補助金,  研究代表者

• 肺動脈性高血圧症の進展を抑制する細胞内カルシウムシグナルの解明

  2014年04月

  -

  2017年03月

  文部科学省・日本学術振興会, 科学研究費助成事業, 内田　敬子, 基盤研究(C), 補助金,  研究代表者

  　研究概要を見る

  長期低酸素暴露による肺高血圧症の程度を野生型と2型イノシトール三リン酸受容体(IP3R2)ノックアウト(KO)マウスで比較したところ、心エコーによる右心機能、右心室の相対的重量による右室肥大、肺組織切片における肺動脈中膜肥厚の全てにおいて、KOマウスでは肺高血圧症が増悪していた。
  IP3R2は肺内では肺動脈平滑筋に特異的に発現しており、肺動脈平滑筋のアポトーシス抵抗性が亢進し、カルシウム流入分子の一つであるTRPc4の発現が上昇していた。さらに、単離肺動脈平滑筋細胞初代培養において、ストア感受性Ca2+流入活性が亢進しており、肺動脈性肺高血圧を増悪させている主な原因経路の一つと考えられた。

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• 現代社会と医学Ⅱ

  2023年度

• 現代社会と医学Ⅰ

  2022年度

• 現代社会と医学Ⅰ

  2021年度

• 現代社会と医学Ⅱ

  2020年度

• 現代社会と医学Ⅱ

  2019年度