Heterogeneity of hypoxic Ca2+ release in pulmonary and *

肺和 * 中缺氧 Ca2 释放的异质性

基本信息

批准号：
7104320
负责人：
YONG-XIAO WANG
金额：
$ 38.57万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-19 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7104320
关键词：
artery calcium channel calcium flux confocal scanning microscopy gene expression gene targeting genetically modified animals hypoxia laboratory mouse membrane activity muscle cells protein structure function pulmonary artery receptor coupling vascular smooth muscle vasoconstriction voltage /patch clamp

项目摘要

DESCRIPTION (provided by applicant): Hypoxia induces [Ca2+]I increase and associated vasoconstriction in pulmonary artery smooth muscle cells (PASMCs), but not in systemic artery myocytes. Futhermore, hypoxic Ca2+ and contractile responses are much greater in resistance than conduit PASMCs. However, very little is known about the cellular and molecular mechanisms underlying these functional differences. We and other investigators have consistently demonstrated that ryanodine receptor (RyR) Ca2+ release is critical for hypoxic [Ca2+]I increase and associated vasoconstriction in PASMCs. Our preliminary studies, together with previous findings, suggest that specific RyR subtypes (RyR1, RyR2 and RyR3) are differentially expressed in the vasculature. This heterogeneous nature of expression may contribute to observed differences in excitation-contraction coupling and hypoxic Ca2+ and contractile responses in various blood vessels. In addition, specific interactions of endogenous regulatory molecules FKBP12.6 (RyR inhibitor) and cADPR (RyR activator with distinct RyR subtypes may also play an important role in the heterogeneity of physiological and hypoxic Ca2+ release and vasoconstriction. To address these hypotheses, this proposal seeks to examine the following three questions (Specific Aims): Are RyR subtypes heterogeneously expressed in resistance and conduit pulmonary and mesenteric artery SMCs? 2) Is RyR Ca2+ release heterogeneous in resistance and conduit pulmonary and mesenteric artery SMCs? 3) Do the heterogeneities of RyR subtypes expression and RyR coupling to FKBP12.6 and cADPR explain differences in hypoxic Ca2+ release between resistance and conduit pulmonary and mesenteric artery SMCs? These aims will be pursued by using the state-of-the-art biophysical (confocal microscopy, patch clamp, etc), molecular and genetic approaches (gene knockout and over-expression). Thus, the findings from this proposal will extend our understanding of the cellular and molecular mechanisms that contribute to the differences and heterogeneity of physiological and hypoxic Ca2+ and contractile responses, and may identify novel therapeutic targets for pulmonary hypertension. The proposed studies are also of fundamental physiological significance with respect to the regulation of Ca2+ release in other cell types.

描述（由申请人提供）：缺氧诱导[Ca2+] I增加，并在肺动脉平滑肌细胞（PASMC）中增加和相关的血管收缩，但不能在全身动脉心肌细胞中增加。与导管PASMC相比，耐药性Ca2+和收缩反应的缺氧反应要大得多。但是，关于这些功能差异的基础的细胞和分子机制知之甚少。我们和其他研究人员一直表明，瑞氨烷受体（RYR）Ca2+释放对于低氧[Ca2+] I增加和相关的PASMC的血管收缩至关重要。我们的初步研究以及先前的发现表明，特定的RYR亚型（RYR1，RYR2和RYR3）在脉管系统中差异表达。表达的这种异质性可能会导致观察到的各种血管中的激发反应耦合以及低氧Ca2+和收缩反应的差异。此外，内源性调节分子FKBP12.6（RYR抑制剂）和CADPR（具有不同RYR亚型的RYR激活剂也可能在生理和低氧CA2+释放和缺血释放和血管施加的异质性中起重要作用，以解决这些假设（特定于三个问题），这是三个问题：在电阻和导管肺动脉和肠系膜动脉SMC中表达？ 3）RYR亚型表达和RYR偶联与FKBP12.6和CADPR的异质性是否解释了电阻和导管肺动脉和肠系膜动脉SMC之间缺氧Ca2+释放的差异？这些目标将通过使用最先进的生物物理（共聚焦显微镜，斑块夹等），分子和遗传方法（基因敲除和过表达）来追求这些目标。因此，该提案的发现将扩展我们对有助于生理和低氧CA2+和收缩反应的差异和异质性的细胞和分子机制的理解，并可能识别出新的肺动脉高压治疗靶标。相对于其他细胞类型中Ca2+释放的调节，拟议的研究也具有基本的生理意义。