MODELS FOR GENETIC DISORDERS OF CALCIUM TRANSPORT
钙转运遗传疾病模型
基本信息
- 批准号:6490635
- 负责人:
- 金额:$ 46.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-01-01 至 2003-12-31
- 项目状态:已结题
- 来源:
- 关键词:calcium flux calcium indicator calcium transporting ATPase disease /disorder model embryonic stem cell genetic models genetically modified animals heart function histogenesis laboratory mouse lung model design /development molecular pathology muscle tone mutant protein structure function respiratory function sarcoplasmic reticulum smooth muscle vascular smooth muscle vasomotion
项目摘要
The long-term objective of this proposal is to develop a detailed
understanding of the role of specific Ca/2+ pumps in cardiovascular and
pulmonary physiology in vivo. The Ca/2+-transporting ATPases being studied
are the sarco(endo)plasmic reticulum Ca/2+-ATPases (SERCAs), which
sequester Ca/2+ in intracellular storage organelles, and the plasma
membrane Ca/2+-ATPases (PMCAs), which extrude Ca/2+ from the cell.
It is clear that SERCAs and PMCAs serve as effector molecules controlling
critical aspects of Ca/2+ homeostasis and signaling, and excitation-
contraction coupling in muscle; however, the specific roles of individual
isoforms are poorly understood. To obtain this information we are
developing mouse models with mutations in each of the Ca/2+ pumps. We have
prepared mice with SERCA2, SERCA3, and PMCA2 null mutations, and have
demonstrated defective cardiac function in SERCA2 heterozygous mutants and
defective endothelium and epithelium dependent relaxation of vascular and
pulmonary smooth muscle in SERCA3 null mutants. In aim 1 we will develop
mice with null mutations in the PMCA1 and PMCA4 genes, and will also
develop a mouse with a modified PMCA1 gene that will produce only the
ubiquitous PMCA1b variant, and not the variants with an acidic calmodulin
binding domain that are restricted to excitable tissues. These experiments
will test the general hypotheses that individual Ca/2+ pumps serve
essential housekeeping on organ-specific functions, and may reveal
unexpected phenotypes that yield insights regarding the specific functions
of these pumps. In aim 2 we will analyze the developmental and
histopathological consequences of mutations in each of the Ca/2+ pumps,
and will perform studies using both the intact animal and isolated tissues
to assess the physiological role of these pumps in cardiovascular and
pulmonary tissues. These experiments will test the hypotheses that SERCA
and PMCA pumps regulate cardiac contractility and pulmonary and vascular
smooth muscle tone and contractility, which in turn affects cardiac
function, airway resistance, and arterial blood pressure. We anticipate
that the six mutant mouse lives developed in this proposal will become
valuable models for analysis of the mechanisms by which Ca/2+-transporting
ATPases modulate physiological functions of cardiovascular, pulmonary, and
other tissues.
这项建议的长期目标是制定一个详细的
了解特异性Ca/2+泵在心血管和
体内肺生理学。正在研究的Ca/2+转运ATP酶
肌浆网Ca/2+-ATP酶(SERCAs),
螯合细胞内储存细胞器和血浆中的Ca/2+
膜Ca/2+-ATP酶(PMCAs),其将Ca/2+从细胞中挤出。
很明显,SERCA和PMCAs作为效应分子,
Ca/2+稳态和信号传导的关键方面,以及兴奋-
肌肉中的收缩耦合;然而,个体的特定作用
对同种型了解甚少。为了获得这些信息,我们
开发在每个Ca/2+泵中具有突变的小鼠模型。我们有
制备具有SERCA 2、SERCA 3和PMCA 2无效突变的小鼠,并且具有
在SERCA 2杂合突变体中证实了心脏功能缺陷,
血管内皮和上皮依赖性舒张缺陷,
SERCA 3无效突变体中的肺平滑肌。在目标1中,我们将开发
在PMCA 1和PMCA 4基因中具有无效突变的小鼠,
开发一种带有修饰的PMCA 1基因的小鼠,
普遍存在的PMCA 1b变体,而不是具有酸性钙调蛋白的变体
限制在可兴奋组织的结合域。这些实验
将检验单个Ca/2+泵的一般假设,
对器官特定功能的基本管家,并可能揭示
意想不到的表型,产生关于特定功能的见解
这些泵。在目标2中,我们将分析发展和
每个Ca/2+泵突变的组织病理学后果,
并将使用完整动物和分离组织进行研究
为了评估这些泵在心血管疾病中的生理作用,
肺组织这些实验将测试SERCA的假设,
和PMCA泵调节心脏收缩力以及肺和血管
平滑肌张力和收缩力,进而影响心脏
功能、气道阻力和动脉血压。我们预计
这六种突变小鼠的生命将成为
对分析Ca/2+转运机制有价值的模型
ATP酶调节心血管、肺和心血管系统的生理功能。
其他组织。
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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GARY EDWARD SHULL其他文献
GARY EDWARD SHULL的其他文献
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{{ truncateString('GARY EDWARD SHULL', 18)}}的其他基金
RENAL SODIUM TRANSPORTERS IN CONTROL OF ARTERIAL BLOOD PRESSURE
肾钠转运蛋白控制动脉血压
- 批准号:
6202277 - 财政年份:1999
- 资助金额:
$ 46.2万 - 项目类别:
Mouse Models for Ion Homeostasis Defects in Heart
心脏离子稳态缺陷的小鼠模型
- 批准号:
7923967 - 财政年份:1999
- 资助金额:
$ 46.2万 - 项目类别:
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