Gap Junctions in Cell-Cell Communication (Supplement)
细胞间通讯中的间隙连接(补充)
基本信息
- 批准号:6645274
- 负责人:
- 金额:$ 9.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1995
- 资助国家:美国
- 起止时间:1995-01-01 至 2005-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): This is a proposal for a Competing Supplement to NHLBI grant #HL53318, Intercellular Communication in Microvessels. The overarching hypotheses or themes are that smooth muscle and endothelium function as an integrated unit in the regulation of cardiovascular function, and 2.) that the coordinating molecule uniting the two cell types is the connexin. The parent R-01 proposes to study three of the connexins; 43, 40, and 37. Knockout animals for connexin 40 and 37 have been obtained from a collaborator. Because deletion of the connexin 43 is embryologically lethal, we have created cell-specific knockouts in which connexin 43 expression is selectively eliminated in either smooth muscle or endothelium. At the time of submission of the parent R-01 grant we indicated that fuller understanding of the biology of the connexins in the vessel wall would necessitate the production of double knockouts through appropriate cross breeding. We selected connexin 43 and 40 as the first double knockout to be produced based on the facts that we could restrict deletion of 43 to the endothelium, and that our immuno-cytochemistry shows connexin 40 in the mouse to be abundantly expresses in the endothelium compared to the other connexins. We have now found that the endothelial cell-specific Cx43 KO crossed with the Cx40 KO produces rapidly advancing hypertension, profound cardiac hypertrophy and failure at about 3 months of age. The phenotype appears to be a model for overload cardiac hypertrophy and failure. Importantly, animal heterozygous for the endothelial cell deletion show a similar phenotype attesting to the penetrance of the phenotype. We have established a collaboration with the cardiac MRI group here and are now able to measure the progression of cardiac adaptation and failure in this model. These data support the need for an accelerated breeding program to designed to generate sufficient double knockouts, and to apply high throughput screening to the assessment of function. The specific aims of the Competing Supplement are: 1. to expand our breeding and animal maintenance to allow us to explore the vascular function in animals with double connexin knockouts. 2. to conduct longitudinal measurements on changes in cardiovascular physiology caused by the elimination of one or more of the connexin genes. Specifically, we will follow blood pressure, cardiac output, heart rate, EKG, and peripheral resistance, over several months of the development of hypertension, cardiac hypertrophy and ultimately failure. These data will be correlated with our ongoing measurements of microvascular function.
描述(由申请人提供):这是 NHLBI 拨款 #HL53318“微血管细胞间通讯”的竞争补充提案。首要的假设或主题是平滑肌和内皮在心血管功能的调节中作为一个整合单元发挥作用,2.) 连接两种细胞类型的协调分子是连接蛋白。母体 R-01 提议研究其中三种连接蛋白; 43、40 和 37。连接蛋白 40 和 37 的敲除动物已从合作者处获得。由于连接蛋白 43 的缺失在胚胎学上是致命的,因此我们创建了细胞特异性敲除,其中连接蛋白 43 的表达在平滑肌或内皮细胞中被选择性消除。 在提交母体 R-01 资助时,我们指出,为了更全面地了解血管壁连接蛋白的生物学特性,需要通过适当的杂交育种来产生双敲除。我们选择连接蛋白 43 和 40 作为第一个双敲除,基于以下事实:我们可以将 43 的缺失限制在内皮细胞中,并且我们的免疫细胞化学显示,与小鼠相比,连接蛋白 40 在内皮细胞中大量表达。其他连接蛋白。我们现在发现,内皮细胞特异性 Cx43 KO 与 Cx40 KO 杂交会导致快速进展的高血压、严重的心脏肥大以及约 3 个月大时的衰竭。该表型似乎是超负荷心脏肥大和衰竭的模型。重要的是,内皮细胞缺失的杂合动物表现出相似的表型,证明了该表型的外显率。我们已经与心脏 MRI 小组建立了合作,现在能够测量该模型中心脏适应和衰竭的进展。这些数据支持需要加速育种计划,以产生足够的双敲除,并将高通量筛选应用于功能评估。竞争补充品的具体目标是: 1. 扩大我们的育种和动物饲养,使我们能够探索双连接蛋白敲除动物的血管功能。 2.对消除一种或多种连接蛋白基因引起的心血管生理学变化进行纵向测量。具体来说,我们将在几个月的高血压、心脏肥大和最终衰竭的发展过程中跟踪血压、心输出量、心率、心电图和外周阻力。这些数据将与我们正在进行的微血管功能测量相关。
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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BRIAN R DULING其他文献
BRIAN R DULING的其他文献
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{{ truncateString('BRIAN R DULING', 18)}}的其他基金
Neutrophil Trafficking to Normal and Inflamed Lung
中性粒细胞转运至正常肺和发炎肺
- 批准号:
7415117 - 财政年份:2007
- 资助金额:
$ 9.94万 - 项目类别:
Neutrophil Trafficking to Normal and Inflamed Lung
中性粒细胞转运至正常肺和发炎肺
- 批准号:
7232630 - 财政年份:2006
- 资助金额:
$ 9.94万 - 项目类别:
Neutrophil Trafficking to Normal and Inflamed Lung
中性粒细胞转运至正常肺和发炎肺
- 批准号:
7062084 - 财政年份:2005
- 资助金额:
$ 9.94万 - 项目类别:
Neutrophil Trafficking to Normal and Inflamed Lung
中性粒细胞转运至正常肺和发炎肺
- 批准号:
6946739 - 财政年份:2004
- 资助金额:
$ 9.94万 - 项目类别:
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