COBRE: UNV MED SCH: P2: CAM KINASE II IN SMOOTH MUSCLE PLASTICITY

COBRE：UNV MED SCH：P2：平滑肌可塑性中的 CAM 激酶 II

• 批准号: 7382017
• 负责人: Brian A Perrino
• 金额: $ 21.19万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382017
• 关键词: COBRE; UNV; MED; SCH; P2

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gastrointestinal smooth muscles adapt contractile activities in response to continuously changing conditions. Mechanical plasticity, such as hypertrophy, alters the functional capacity of smooth muscles in response to changing demands by reorganizing contractile bundles. The amplitude and frequency of cytosolic Ca 2+ oscillations encodes information that is translated into physiological responses. CaM kinase II has the structural, catalytic, and regulatory properties required of a molecular decoder of Ca 2+ oscillations. Fundus and colon smooth muscles, which exhibit distinct Ca 2¿ oscillations, express CaM kinase II holoenzymes with tissue-specific enzymatic properties. In situ hybridization, kinase assays, Western blotting, and ratiometric Ca 2¿ imaging will be used to investigate how CaM kinase II responds to cytosolic Ca 2¿ transients in order to understand how it modulates smooth muscle contractile activity. Hypertrophy of gastrointestinal smooth muscles due to obstructions of the digestive tract resulting from congenital or acquired defects is associated with pathologies that lead to several motility disorders. Part of the cell volume increase results from elevated transcription and expression of contractile proteins under the control of serum response factor. Serum response factor is activated by CaM kinase II phosphorylation. Fundus and colon smooth muscles express CaM kinase II splice variants containing a nuclear localization signal. Cellular fractionation, Western blotting, kinase assays, Q-PCR, phosphopeptide mapping, and expression proteomics will be used to elucidate the role of CaM kinase II in the activation of contractile protein gene transcription by serum response factor. Gastrointestinal smooth muscle hypertrophy is important in normal physiology and disease. This project will explore the regulation and physiological roles of CaM kinase II in normal agonist-stimulated, and abnormal hypertrophied gastrointestinal smooth muscles. Determining the enzymatic characteristics of gastrointestinal smooth muscle CaM kinase II and investigating the modulation of gastrointestinal smooth muscle contraction by CaM kinase II will provide additional information for developing better therapeutics aimed at treating the myogenic component of the altered motility patterns that underlie digestive tract motility disorders.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。胃肠道平滑肌适应不断变化的条件下的收缩活动。机械可塑性，如肥大，通过重组收缩束来改变平滑肌的功能能力，以响应不断变化的需求。胞质ca2 +振荡的振幅和频率编码了转化为生理反应的信息。CaM激酶II具有ca2 +振荡分子解码器所需的结构、催化和调节特性。眼底和结肠平滑肌表现出明显的ca2¿振荡，表达具有组织特异性酶特性的CaM激酶II全酶。原位杂交、激酶测定、Western blotting和比例钙离子成像将用于研究CaM激酶II如何响应胞质钙离子瞬变，以了解它如何调节平滑肌收缩活性。由先天性或后天缺陷引起的消化道阻塞引起的胃肠道平滑肌肥大与导致多种运动障碍的病理有关。细胞体积增加的部分原因是在血清反应因子的控制下，收缩蛋白的转录和表达升高。血清反应因子是由CaM激酶II磷酸化激活的。眼底和结肠平滑肌表达含有核定位信号的CaM激酶II剪接变异体。细胞分离、Western blotting、激酶测定、Q-PCR、磷酸肽定位和表达蛋白质组学将被用来阐明CaM激酶II在通过血清反应因子激活收缩蛋白基因转录中的作用。胃肠平滑肌肥大在正常生理和疾病中具有重要意义。本项目将探讨CaM激酶II在正常激动剂刺激及异常肥大胃肠道平滑肌中的调节及生理作用。确定胃肠道平滑肌CaM激酶II的酶学特性和研究CaM激酶II对胃肠道平滑肌收缩的调节将为开发更好的治疗方法提供额外的信息，旨在治疗消化道运动障碍背后的运动模式改变的肌源性成分。