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: 7036585
• 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/7036585
• 关键词: calcium channel; calcium flux; cardiovascular disorder risk; coronary artery; coronary disorder; disease /disorder model; estradiol; female; fluorimetry; gender difference; hormone regulation /control mechanism; ion channel blocker; male; miniature swine; organ culture; pathologic process; potassium channel; protein kinase C; testosterone; vascular smooth muscle; vasomotion; vasospasm; voltage /patch clamp; voltage gated channel; western blottings

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）：我的长期职业目标是继续努力在适应性冠状动脉生理学领域取得卓越的学术和研究成果，重点是了解离子通道在健康和疾病期间调节冠状血管反应性和表型调节的作用。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的转化方法来追求新的假设。拟议的研究职业奖将提供机会集中时间、精力和资源来开发和完善这种综合方法所需的技术范围，从而有助于实现这种综合方法。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真正独特的环境。拟议的大部分研究将集中于性激素对冠状血管系统的影响，特别是在细胞/分子水平上。性激素对血管平滑肌生理学产生深远影响，包括增殖、离子通道活性和通道表达。冠状动脉平滑肌（CSM）离子通道活性对于冠状动脉血流的调节和血管疾病的进展至关重要。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 通道活性的性别特异性差异的机制，以及对细胞内钙 ([Cai]) 调节和血管反应性的后续影响。总体假设是，由于睾酮（TST）依赖性的 VGCC 合成增加和冠状血管痉挛（CVS）倾向增强，男性冠状动脉反应性更强。体内（完整的、去性腺切除的和激素替代的猪）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。冠状血管痉挛模型将用于评估 VGCC 活性的性别特异性差异对血管疾病的进展和严重程度的作用。本研究的目的是确定 CSM 中与性别相关的细胞和分子差异，因为它们与冠心病倾向的性别差异有关。