内田 敬子 (ウチダ ケイコ)

Uchida, Keiko

写真a

所属(所属キャンパス)

研究所・センター等 保健管理センター (日吉)

職名

准教授(有期)

経歴 【 表示 / 非表示

  • 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

学歴 【 表示 / 非表示

  • 1988年04月
    -
    1994年03月

    慶應義塾, 医学部

    日本, 大学, 卒業

学位 【 表示 / 非表示

  • 博士(医学), 慶應義塾, 論文, 2005年12月

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

  • 小児科学

  • 発生生物学

  • 細胞生物学

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

  • 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

  • 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

  • Association of childhood anthropometric measurements and laboratory parameters with high blood pressure in young adults

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

    Hypertension Research (Hypertension Research)  44 ( 6 ) 711 - 719 2021年06月

    ISSN  09169636

     概要を見る

    Early intervention to manage high blood pressure (BP) in young adulthood is a promising approach for the prevention of future cardiovascular diseases. We aimed to examine the ability of childhood health information to predict the incidence of young adults with high BP. This cohort study included baseline clinical data of Japanese individuals aged 12–13 years. A total of 1129 participants were followed up for an average of 8.6 years. We examined the association of childhood variables consisting of body weight, body mass index, systolic BP, white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count, uric acid, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol with the development of high BP defined as ≥120/80 mmHg at 18–22 years old. At follow-up, the prevalence of high BP was 42.2% in men and 7.7% in women. Young men with high BP had childhood baseline characteristics that included higher body weight, body mass index, systolic BP, red blood cell count, hemoglobin, hematocrit, and uric acid than normotensive men. Young women with high BP had higher body weight, systolic BP, and uric acid at baseline. Multivariable logistic regression analysis revealed that a model including body weight, systolic BP, hematocrit, and uric acid had the highest predictive power (AUC 0.65 [95% CI, 0.62–0.69]) for men, and a model including body weight, systolic BP, and uric acid had the highest predictive power (AUC 0.70 [95% CI, 0.58–0.81]) for women. Comprehensive childhood health information contributes to the prediction of high BP in young adults.

  • Genetic and Cellular Interaction During Cardiovascular Development Implicated in Congenital Heart Diseases

    Kodo K., Uchida K., Yamagishi H.

    Frontiers in Cardiovascular Medicine (Frontiers in Cardiovascular Medicine)  8 2021年03月

     概要を見る

    Congenital heart disease (CHD) is the most common life-threatening congenital anomaly. CHD occurs due to defects in cardiovascular development, and the majority of CHDs are caused by a multifactorial inheritance mechanism, which refers to the interaction between genetic and environmental factors. During embryogenesis, the cardiovascular system is derived from at least four distinct cell lineages: the first heart field, second heart field, cardiac neural crest, and proepicardial organ. Understanding the genes involved in each lineage is essential to uncover the genomic architecture of CHD. Therefore, we provide an overview of recent research progress using animal models and mutation analyses to better understand the molecular mechanisms and pathways linking cardiovascular development and CHD. For example, we highlight our recent work on genes encoding three isoforms of inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) that regulate various vital and developmental processes, which have genetic redundancy during cardiovascular development. Specifically, IP3R1 and 2 have redundant roles in the atrioventricular cushion derived from the first heart field lineage, whereas IP3R1 and 3 exhibit redundancy in the right ventricle and the outflow tract derived from the second heart field lineage, respectively. Moreover, 22q11.2 deletion syndrome (22q11DS) is highly associated with CHD involving the outflow tract, characterized by defects of the cardiac neural crest lineage. However, our studies have shown that TBX1, a major genetic determinant of 22q11DS, was not expressed in the cardiac neural crest but rather in the second heart field, suggesting the importance of the cellular interaction between the cardiac neural crest and the second heart field. Comprehensive genetic analysis using the Japanese genome bank of CHD and mouse models revealed that a molecular regulatory network involving GATA6, FOXC1/2, TBX1, SEMA3C, and FGF8 was essential for reciprocal signaling between the cardiac neural crest and the second heart field during cardiovascular development. Elucidation of the genomic architecture of CHD using induced pluripotent stem cells and next-generation sequencing technology, in addition to genetically modified animal models and human mutation analyses, would facilitate the development of regenerative medicine and/or preventive medicine for CHD in the near future.

  • Changes in epidemiological characteristics and sero-prevalence against the varicella zoster virus in school-age children after the introduction of a national immunization program in Japan

    Yasui Y., Mitsui T., Arima F., Uchida K., Inokuchi M., Tokumura M., Nakayama T.

    Human Vaccines and Immunotherapeutics (Human Vaccines and Immunotherapeutics)  2021年

    ISSN  21645515

     概要を見る

    A national immunization program using two doses of live attenuated varicella vaccine was introduced for children aged one to two years in Japan in October 2014. Varicella cases declined after 2014, and immunological status against varicella among vaccinated children changed in post-vaccination era. A retrospective observational study of anti-varicella antibody seroprevalence, varicella vaccination status, and history of varicella among 528 students in the first grade of elementary school was conducted. The percentage of students who received at least a single dose of varicella vaccination increased from 67% (187 of 279 students) in 2007–2008 to 91% (226 of 249 students) in 2017. Students with a history of varicella decreased from 114 of 279 (41%) in 2007–2008 to 48 of 249 (19%, P < .01) in 2017. Among them, the rate of breakthrough varicella after a single dose of vaccine in students with a history of varicella significantly increased from 38% (43 of 114 students) in 2007–2008 to 58% (28 of 48 students) in 2017 (P < .05). The antibody-positive rate significantly decreased from 50% among subjects without varicella zoster who received a single dose (95%CI: 41–58%) in 2007–2008 to 29% (95%CI: 21–38%) in 2017 (P < .01). The antibody-positive rate among students without varicella history who received two doses of vaccine was only 43% (95%CI: 32–55%) in 2017. The number of varicella infections and antibody-positive rate among students without history of varicella who received varicella vaccination decreased after the introduction of a national immunization program.

  • Inositol 1,4,5-trisphosphate receptor 2 as a novel marker of vasculature to delineate processes of cardiopulmonary development

    Ishizaki-Asami R., Uchida K., Tsuchihashi T., Shibata A., Kodo K., Emoto K., Mikoshiba K., Takahashi T., Yamagishi H.

    Developmental Biology (Developmental Biology)  458 ( 2 ) 237 - 245 2020年02月

    ISSN  00121606

     概要を見る

    Congenital heart diseases (CHDs) involving the outflow tract (OFT), such as persistent truncus arteriosus (PTA), lead to mortality and morbidity with implications not only in the heart, but also in the pulmonary vasculature. The mechanisms of pulmonary artery (PA) development and the etiologies underlying PA disorders associated with CHD remain poorly understood partly because of a specific marker for PA development is nonexistent. The three subtypes of inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) are intracellular Ca2+ channels that are essential for many tissues and organs. We discovered that IP3R2 was expressed in the vasculature and heart during development using transgenic mice, in which a LacZ marker gene was knocked into the IP3R2 locus. Whole-mount and section LacZ staining showed that IP3R2-LacZ-positive cells were detectable exclusively in the smooth muscle cells, or tunica media, of PA, merging into αSMA-positive cells during development. Furthermore, our analyses suggested that IP3R2-LacZ positive PA smooth muscle layers gradually elongate from the central PA to the peripheral PAs from E13.5 to E18.5, supporting the distal angiogenesis theory for the development of PA, whereas IP3R2-LacZ was rarely expressed in smooth muscle cells in the pulmonary trunk. Crossing IP3R-LacZ mice with mice hypomorphic for Tbx1 alleles revealed that PTA of Tbx1 mutants may result from agenesis or hypoplasia of the pulmonary trunk; thus, the left and right central to peripheral PAs connect directly to the dorsal side of the truncus arteriosus in these mutants. Additionally, we found hypercellular interstitial mesenchyme and delayed maturation of the lung endoderm in the Tbx1 mutant lungs. Our study identifies IP3R2 as a novel marker for clear visualization of PA during development and can be utilized for studying cardiopulmonary development and disease.

  • Type 2 inositol 1,4,5-trisphosphate receptor inhibits the progression of pulmonary arterial hypertension via calcium signaling and apoptosis

    Shibata A., Uchida K., Kodo K., Miyauchi T., Mikoshiba K., Takahashi T., Yamagishi H.

    Heart and Vessels (Heart and Vessels)  34 ( 4 ) 724 - 734 2019年04月

    ISSN  09108327

     概要を見る

    Pulmonary arterial hypertension (PAH) is a progressive disease associated with vasoconstriction and remodeling. Intracellular Ca 2+ signaling regulates the contraction of pulmonary arteries and the proliferation of pulmonary arterial smooth muscle cells (PASMCs); however, it is not clear which molecules related to Ca 2+ signaling contribute to the progression of PAH. In this study, we found the specific expression of type 2 inositol 1,4,5-trisphosphate receptor (IP 3 R2), which is an intracellular Ca 2+ release channel, on the sarco/endoplasmic reticulum in mouse PASMCs, and demonstrated its inhibitory role in the progression of PAH using a chronic hypoxia-induced PAH mouse model. After chronic hypoxia exposure, IP 3 R2 −/− mice exhibited the significant aggravation of PAH, as determined by echocardiography and right ventricular hypertrophy, with significantly greater medial wall thickness by immunohistochemistry than that of wild-type mice. In IP 3 R2 −/− murine PASMCs with chronic hypoxia, a TUNEL assay revealed the significant suppression of apoptosis, whereas there was no significant change in proliferation. Thapsigargin-induced store-operated Ca 2+ entry (SOCE) was significantly enhanced in IP 3 R2 −/− PASMCs in both normoxia and hypoxia based on in vitro fluorescent Ca 2+ imaging. Furthermore, the enhancement of SOCE in IP 3 R2 −/− PASMCs was remarkably suppressed by the addition of DPB162-AE, an inhibitor of the stromal-interacting molecule (STIM)–Orai complex which is about 100 times more potent than 2-APB. Our results indicate that IP 3 R2 may inhibit the progression of PAH by promoting apoptosis and inhibiting SOCE via the STIM–Orai pathway in PASMCs. These findings suggest a previously undetermined role of IP 3 R in the development of PAH and may contribute to the development of targeted therapies.

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競争的資金等の研究課題 【 表示 / 非表示

  • 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,  代表

  • 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,  代表

  • 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,  代表

     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。

 

担当授業科目 【 表示 / 非表示

  • 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