Preterm labour prevention: composition and characterisation of the predominate KV7 channel subunits in human uterine tissue and smooth muscle cells
早产预防:人子宫组织和平滑肌细胞中主要 KV7 通道亚基的组成和特征
基本信息
- 批准号:2444537
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:英国
- 项目类别:Studentship
- 财政年份:2020
- 资助国家:英国
- 起止时间:2020 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Despite spontaneous preterm birth being a major contributor to perinatal morbidity and mortality worldwide, it cannot be accurately predicted or prevented or treated. Our research into the control of uterine contractility has led us to propose potassium channels encoded by KCNQ2-5 genes (KV7 channels) as a potential drug target to inhibit preterm uterine contractions and potentially immune cell activation. Only specific KCNQ1-5 and accessory KCNE1-5 are functionally expressed in pregnant human uterine tissue (myometrium) from women at term and in labour. Pharmacological activation of Kv7 channels inhibit pregnant human and mouse myometrium contractions in vitro, with ML213 (a KV7.4/ KV7.4, KV7.2and Kv7.5 preferential activator) being the most effective. Kv7 channel activators delay preterm birth in an experimental model. This provides essential 'proof of principle' data for functional KV7 channels in human myometrium and highlights the potential of KV7 channel activators to inhibit uterine contractions and preterm delivery. The aim of this PhD project is to determine the specific architecture of the human uterine KV7 channel and its interactions with KCNE proteins as well as aspects of KV7.4 channel regulation and trafficking in human myometrium tissue and cells. A secondary aim is to determine uterine cell type differences in Kv7 expression in order to understand potential pharmacological impact (e.g. immune cells). A variety of imaging and molecular techniques will be used including using super resolution confocal imaging, multiphoton microscopy, structural illumination imaging, gene knockdown and overexpression, and RNAseq. The project has flexibility to focus more on protein structure, cellular regulation and gen e manipulation or membrane biophysics approaches depending on candidate interest/skill set. Training will be provided in both supervisors' well-equipped research facilities/laboratories. The student will have access to KCL core and BRC facilities (e.g. Nikon Imaging Centre and BRC Flow cytometry and genomics platforms), relevant personal development training, and journal clubs and seminars.
尽管自发性早产是全世界围产期发病率和死亡率的主要原因,但无法准确预测或预防或治疗。我们对子宫收缩控制的研究使我们提出KCNQ 2 -5基因编码的钾通道(KV 7通道)作为抑制早产子宫收缩和潜在免疫细胞激活的潜在药物靶点。只有特定的KCNQ 1 -5和辅助KCNE 1 -5在足月和分娩妇女的妊娠子宫组织(子宫肌层)中功能性表达。Kv 7通道的药理学激活在体外抑制怀孕的人和小鼠子宫肌层收缩,其中ML 213(Kv7.4/ Kv7.4、Kv7.2和Kv7.5优先激活剂)是最有效的。Kv 7通道激活剂在实验模型中延迟早产。这为人类子宫肌层中功能性KV 7通道提供了基本的“原理证明”数据,并突出了KV 7通道激活剂抑制子宫收缩和早产的潜力。该博士项目的目的是确定人类子宫KV 7通道的特定结构及其与KCNE蛋白的相互作用,以及KV7.4通道调节和人类子宫肌层组织和细胞中的贩运方面。次要目的是确定Kv 7表达的子宫细胞类型差异,以了解潜在的药理学影响(例如免疫细胞)。将使用各种成像和分子技术,包括使用超分辨率共聚焦成像,多光子显微镜,结构照明成像,基因敲低和过表达,以及RNAseq。该项目具有灵活性,可以更多地关注蛋白质结构,细胞调控和基因操纵或膜生物物理学方法,这取决于候选人的兴趣/技能集。培训将在两名主管设备齐全的研究设施/实验室进行。学生将有机会使用KCL核心和BRC设施(例如尼康成像中心和BRC流式细胞术和基因组学平台),相关的个人发展培训,以及期刊俱乐部和研讨会。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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其他文献
吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
- DOI:
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- 影响因子:0
- 作者:
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LiDAR Implementations for Autonomous Vehicle Applications
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
- DOI:
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Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
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