NYP INTERACTION WITH MICROVASCULR ENDOTHELIUM
NYP 与微血管内皮的相互作用
基本信息
- 批准号:6395890
- 负责人:
- 金额:$ 13.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-01-01 至 2000-12-31
- 项目状态:已结题
- 来源:
- 关键词:SDS polyacrylamide gel electrophoresis adenylate cyclase animal tissue biological signal transduction calcium channel calcium flux cyclic AMP electrophysiology enzyme activity enzyme inhibitors neuropeptide Y nitric oxide phosphorylation potassium channel prostacyclins protein kinase radioimmunoassay receptor binding receptor coupling receptor expression statistics /biometry tissue /cell culture vascular endothelium voltage /patch clamp western blottings
项目摘要
NPY is a 36 amino acid peptide originally discovered in 1982
romextracts of brain tissue. Since its identification, evidence has
been accumulating to favor its role in the regulationof the
cardiovascular system. Most of this activity has been ascribed to
both direct vasoconstriction and its ability to post-synaptically
potentiate other vasoconstrictors action. Other reported regulatory
functions concern NPY modulationof brainstem areas controlling the
autonomic outflow to cardiac and vacular components and its ability
to moduate the release of norepinephrine and other transmitters from
perivascular nerves and the sympathetic and intrinsic nerves at the
heart level. Although limited, there is evidence to support a NPY
modulation at the endothelial level. In large vessel endothelial
models. NPY has been observed in one hand to potentiate leukocyte
adhesion in a time and concentration dependent manner and in the
other hand to modify prostacyclin production. Using an in vitro
model of cultured capillary endothelial cells derived from bovine
adrenal medulla we have reported the presence of high affinity
specific binding sites for NPY and its analogs and have observed that
the neuropeptide is capable of inducing signaling events associated
with NPY receptor activation in other model systems. Moreover, we
have preliminary data to support a comparable signaling responses in
microvascular tissue from bovine retina but not with endothelium
derived from bovine aorta. Our present goal with the following
proposal is to contribute to define the nature of NPY interaction
with the microvascular endothelium. Our general hypothesis is that
NPY receptors are preferentially distributed in capillary endothelium
and that their activation results inthe formation of
endothelialderived vasodilators. In order to prove this hypothesis
we are propsing to carry out the following specific aims: (1)
Evaluate whether NPY receptors are preferentially expressed in other
microvasculatures. This will be achieved by performing radioligand
binding studies with cultured endothelial cells dervied from large
vessels and the microvasculature of several tissues. (2) Test the
hypothesis that NPY induces the release of NO and PGI2 from
microvascular endothelium through the detection of the basal and
stimulated release of these vasodilators in the presence and absence
of the neuropeptide. (3) Evaluate the interaction of NPY induced
calcium response with other signaling cascades implied in the
modulation of endothelial function, specifically (a) the involvement
of protein tyrosine kinase pathways through the assessment of the
effect of proteinkinases inhibitors and the immunodetectionof
phosphorylated proteins upon NPY receptor activation. (b) therole of
Ca2+-activated K+ channels through the performance of patch-clamp
experiments to detect the effect of NPY on the electrophysiologic
parameters associated with the expression of these channels. (4)
Test whether the NPY negative coupling to adenylate cyclase modulates
the stimulated release of NO and PGI2 by measuring the relese of
these agents after manipulations to alter cAMP levels. Altogether
the studies should provide insight into the functional role of NPY at
the level of the microvscular endothelium expanding our understanding
of the regulation of the cardiovascular system provided by this
neuropeptide.
NPY是最初于1982年发现的36个氨基酸肽
脑组织的罗马克提取。 自识别以来,证据已有
一直积累以偏爱其在调节中的作用
心血管系统。 大部分活动都归因于
直接血管收缩及其突触后的能力
增强其他血管收缩的作用。 其他报告的监管
功能涉及控制脑干区域的NPY调节
自主流出到心脏和真空成分及其能力
调节去甲肾上腺素和其他发射机的释放
血管周神经以及在
心脏水平。 尽管有限,但是有证据支持NPY
在内皮水平的调节。 在大容器内皮中
型号。 一只手观察到NPY以增强白细胞
以时间和浓度依赖于粘附方式和
另一只手来修改前列环蛋白的产生。 使用体外
衍生自牛的毛细血管内皮细胞的模型
肾上腺髓质我们报告了高亲和力的存在
NPY及其类似物的特定结合位点,并观察到
神经肽能够诱导相关的信号事件
在其他模型系统中具有NPY受体激活。 而且,我们
有初步数据以支持可比的信号响应
牛视网膜的微血管组织,但没有内皮
源自牛主动脉。 我们目前的目标以下
建议是为定义NPY相互作用的性质做出贡献
与微血管内皮。 我们的总体假设是
NPY受体优先分布在毛细管内皮中
并且它们的激活导致形成
内皮层的血管扩张剂。 为了证明这一假设
我们正在实施以下特定目标:(1)
评估NPY受体是否优先表达在其他
微血管。 这将通过执行放射线来实现
与大型内皮细胞的结合研究
几个组织的血管和微脉管系统。 (2)测试
NPY诱导了NO和PGI2的假设
微血管内皮通过检测基础和
在存在和不存在的情况下刺激这些血管扩张剂的释放
神经肽。 (3)评估NPY诱导的相互作用
钙反应与其他信号级联反应
内皮功能的调节,特别是(a)参与
通过评估的蛋白酪氨酸激酶途径
蛋白氨基酶抑制剂和免疫试验的影响
NPY受体激活后的磷酸化蛋白质。 (b)
CA2+激活的K+通道通过斑块钳的性能
检测NPY对电生理学的影响的实验
与这些通道的表达相关的参数。 (4)
测试NPY负偶联与腺苷酸环化酶是否调节
通过测量RESE的刺激释放NO和PGI2的释放
这些操纵后的这些代理改变了营地水平。 共
研究应洞悉NPY在
微伏尺寸内皮的水平扩大了我们的理解
由此提供的心血管系统的调节
神经肽。
项目成果
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