Coronary ion channels, gender and vasoreactivity

冠状动脉离子通道、性别和血管反应性

• 批准号: 7596326
• 负责人: DOUGLAS K BOWLES
• 金额: $ 10.34万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596326
• 关键词: Acute; Attenuated; Award; Blood Vessels; Blood flow; Calcium; Calcium-Activated Potassium Channel; Cardiovascular system; Cells; Clinical; Coronary; Coronary Artery Vasospasm; Coronary heart disease; Coupled; Coupling; Culture Techniques; Cytophotometry; Disease; Environment; Estradiol; Estrogens; Family suidae; Female; Gender; Gender Role; Gene Expression; Goals; Gonadal Steroid Hormones; Health; Hormones; Immunoblotting; In Vitro; Injury; Ion Channel; Isometric Exercise; Measures; Missouri; Modeling; Molecular; Organ Culture Techniques; Physiological; Physiology; Potassium Channel; Probability; Protein Kinase C; Regulation; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; Severities; Sex Characteristics; Smooth Muscle; Smooth Muscle Myocytes; Techniques; Testosterone; Time; Universities; Vascular Diseases; Vascular Smooth Muscle; career; clinically relevant; dalton; density; in vivo; large-conductance calcium-activated potassium channels; male; novel; patch clamp; response; translational approach; voltage; voltage clamp; voltage gated channel

DESCRIPTION (provided by applicant): My long-term professional goal is to continue to strive for both academic and research excellence in the field of adaptive coronary physiology with a focus on understanding the role of ion channels in regulating coronary vasoreactivity and phenotypic modulation during health and disease. My goal is to develop a truly "vertical" approach to research, from the level of gene expression to translational approaches using in vivo clinical measures to pursue novel hypotheses. The proposed research career award will be instrumental in achieving this integrative approach by offering the opportunity to focus the time, energy and resources to develop and refine the spectrum of techniques necessary for this integrative approach. The University of Missouri and the Dalton Cardiovascular Research Center provide a truly unique environment to achieve these goals. Much of the proposed research will focus on sex hormone effects on the coronary vasculature, especially at the cellular/molecular level. Sex hormones exert profound influence on vascular smooth muscle physiology, including proliferation, ion channel activity and channel expression. Coronary smooth muscle (CSM) ion channel activity is central to both regulation of coronary blood flow and the progression of vascular disease. We have demonstrated that CSM calcium and potassium channel activity are strongly influenced by gender. This study will determine the mechanism for gender-specific differences in CSM voltage-gated calcium (VGCC) and K channel activity and the consequent effects on intracellular calcium ([Cai]) regulation and vasoreactivity. The overall hypothesis is that coronary arterial reactivity in males is greater due to a testosterone (TST)-dependent increase in VGCC synthesis and an enhanced propensity for coronary vasospasm (CVS). Both in vivo (intact, gonadectomized and hormone-replaced swine) and in vitro techniques will be used to determine the role of gender, TST and estrogen (E2) in regulating CSM ion channel activity and coronary arterial reactivity. A model of coronary vasospasm will be used to assess the role of sex-specific differences in VGCC activity on the progression and severity of vascular disease. The goal of this research is to determine gender-related cellular and molecular differences in CSM as they relate to gender differences in propensity for coronary disease.

描述（由申请人提供）：我的长期专业目标是继续在适应性冠状动脉生理学领域取得学术和研究上的卓越成就，重点是了解离子通道在调节健康和疾病期间冠状动脉血管反应性和表型调节中的作用。我的目标是开发一种真正的“垂直”研究方法，从基因表达水平到使用体内临床测量来追求新假设的翻译方法。拟议的研究生涯奖将有助于实现这一综合方法，为集中时间、精力和资源来开发和完善这一综合方法所需的各种技术提供机会。密苏里大学和道尔顿心血管研究中心为实现这些目标提供了一个真正独特的环境。许多拟议的研究将集中在性激素对冠状血管的影响，特别是在细胞/分子水平上。性激素对血管平滑肌的增殖、离子通道活性和通道表达等生理机能有着深远的影响。冠状动脉平滑肌（CSM）离子通道活性是调节冠状动脉血流和血管疾病进展的核心。我们已经证明CSM钙和钾通道活性受性别的强烈影响。本研究将确定CSM电压门控钙（VGCC）和K通道活性的性别差异机制，以及随之对细胞内钙（[Cai]）调节和血管反应性的影响。总的假设是，男性冠状动脉反应性更强是由于睾酮（TST）依赖性VGCC合成增加和冠状血管痉挛（CVS）倾向增加。体内（完整的、去性腺的和激素替代的猪）和体外技术将用于确定性别、TST和雌激素（E2）在调节CSM离子通道活性和冠状动脉反应性中的作用。冠状动脉痉挛模型将用于评估VGCC活性的性别特异性差异在血管疾病进展和严重程度中的作用。本研究的目的是确定CSM中与性别相关的细胞和分子差异，因为它们与冠状动脉疾病倾向的性别差异有关。