REGULATION OF KININ DELIVERY ON HUVEC

构成这一提议基础的假设是 血浆激肽原的内皮细胞受体是一种多聚体 排列接触蛋白酶原组装和激活的结构 用于隔离的激肽释放酶和其他激肽释放酶的前激肽释放酶 依赖的生物活动。激肽原表达均较高(香港) 该受体上的低(LK)分子激肽原允许激动素 [缓激肽(BK)和蛋氨酸缓激肽(Kallidin)]将被解放以 影响局部血管生物学。 这一假设是基于这样的发现：内皮细胞含有 几种膜表达的激肽原结合蛋白。第二，两地都是香港 和LK本身有多个结合域用于其特定的 定位于其内皮细胞结合部位(S)，推定 受体(S)。第三，HK作为血管内皮细胞的结合部位 前激肽释放酶。第四，前激肽释放酶只与内皮上的HK结合 由内皮细胞激活，需要金属蛋白酶的钙 动力学上有利的尿激活酶原和随后的纤溶酶原 激活。 为了检验上述假设，这项提议的具体目标如下 具体如下：(1)内皮细胞激肽原受体(S) 下定决心。(2)S调节细胞释放激动素的机制-- 结合的激肽原将被确定。(3)序列的精细映射 参与其与内皮结合的激肽原将是 特色化的。 这些研究将表征激动素是如何从其 血管内间隔中的亲本蛋白对血管的影响 生物学。这些研究将为调节ALL提供一条新的途径 缓激肽依赖的内皮细胞活动，如tPA释放， NO生成、cGMP升高、前列环素合成、超氧化物歧化 形成，并产生平滑肌超极化因子。 缓激肽释放的调节在调节 冠状动脉、肾脏、肺和脑的局部血压 发行量。

The hypothesis that forms the basis of this proposal is that the endothelial cell receptor for the plasma kininogens is a multimeric structure that orders contact protein zymogen assembly and activation of prokallikreins for sequestered kinin liberation and other kallikrein- dependent biologic activities. Expression of kininogens, both high (HK) and low (LK) molecular mass kininogens on this receptor permits kinins [bradykinin (BK) and met-lys-bradykinin (kallidin)] to be liberated to influence local vascular biology. This hypothesis is based upon the finding that endothelial cells contain several membrane-expressed kininogen binding proteins. Second, both HK and LK themselves have multiple binding-domains for its particular orientation onto its endothelial cell binding site(s), putative receptor(s). Third, HK serves as the endothelial cell binding site for prekallikrein. Fourth, prekallikrein only bound to HK on endothelium is activated by an endothelial cell, calcium requiring metalloprotease for kinetically favorable pro-urokinase and subsequent plasminogen activation. To test the above hypothesis, the specific aims of this proposal are as follows: (1) The kininogen receptor(s) on endothelial cells will be determined. (2) The mechanism(s) regulating kinin liberation from cell- bound kininogens will be determined. (3) The fine mapping of sequences on kininogens that participate in its binding to endothelium will be characterized. These investigations will characterize how kinins are liberated from its parent proteins in the intravascular compartment to influence vascular biology. These studies will provide a new avenue for modulation of all bradykinin-dependent, endothelial cell activities such as tPA liberation, NO formation, elevation of cGMP, prostacyclin synthesis, superoxide formation, and smooth muscle hyperpolarization factor production. Modulation of bradykinin liberation is important in the regulation of local blood pressure in coronary, renal, pulmonary, and cerebral circulations.