MOLECULAR MECHANISMS OF PLATELET ACTIVATION

我们研究的总体目标是描绘生物化学途径 其在由激动剂结合到 表面受体，并导致血小板分泌，激活 纤维蛋白原结合位点和聚集。 作为我正在进行的研究的一部分 在这条调查路线上，我们已经准备并分离出了一种刺激性的 单克隆抗体（M.Ab.），名为F-11。 M.A.B F-11作为激动剂 其诱导人血小板的分泌和聚集。 临床 有充分的文献证明了激活血小板的抗体的重要性，但是 作为受体的表面抗原的详细表征 在这个过程中，由这种抗体触发的生化途径 尚未划定。 我们希望详细的研究M. Ab。F-11 将开始填补这些空白。 使用M.Ab F-11提供了两种不同的 优点：（1）M. Ab识别的蛋白质。血小板上的F-11 表面已确定和部分纯化在我们的实验室。 因此，我们的研究现在集中在一个激活过程， 其分子实体是已知的受体。 (2)的激活 用纯化的M.Ab. F-11的滞后期为6至 20分钟 该延迟期允许对 导致血小板分泌和聚集的一系列分子事件。 因此，在此提交的研究计划旨在实现 以下具体目标：（a）纯化非变性形式的 F-11受体，（B）F-11抗原的表征和研究 至于它是否是一个独特的受体，受体复合物的一部分， 天然存在的血小板激动剂的组分，或已知的 信号转导系统，（c）生化途径的测定 F-11激活血小板的作用，（d） 纯化的F-11受体的多克隆和单克隆抗体， 在血小板F-11抗原的功能结构域中，（e）克隆、测序 以及F-11受体基因的染色体定位。 我们预计 这些研究目标的实现将提供新的， 关于血小板聚集过程中基本机制的重要信息 activation. 这些研究对健康的影响是 特别是与涉及以下相互作用的病理生理状态相关： 抗体与循环血小板。

The overall goal of our research is the delineation of biochemical pathways which operate in the process initiated by the binding of an agonist to surface receptors, and leading to platelet secretion, activation of fibrinogen binding sites and aggregation. As part of my ongoing studies in this line of investigation, we have prepared and isolated a stimulatory monoclonal antibody (M.Ab.), named F-11. M.A.b F-11 acts as an agonist which induces secretion and aggregation of human platelets. The clinical significant of antibodies which activate platelets is well documented, but detailed characterization of the surface antigens that serve as receptors in this process and biochemical pathways triggered by such antibodies has not yet been delineated. We expect that detailed studies of M.Ab. F-11 will begin to fill these gaps. The use of M.Ab F-11 provides two distinct advantages: (1) The protein recognized by M.Ab. F-11 on the platelet surface has been identified and partially purified in our laboratory. Thus, our studies focus now on an activation process initiated by a receptor whose molecular entity is already known. (2) The activation of human platelets by purified IgG of M.Ab. F-11 involves a lag period of 6 to 20 minutes. This latency period permits detailed measurements of the sequence of molecular events leading to platelet secretion and aggregation. Accordingly, the Research Plan submitted here is designed to achieve the following specific goals: (a) Purification of a non-denatured form of the F-11 receptor, (b) characterization of the F-11 antigen and investigation as to whether it is a unique receptor, part of the receptor complex for one of the naturally-occurring platelet agonists, or a component of a known signal transduction system, (c) Determination of the biochemical pathway(s) operating in the activation of platelets by F-11, (d) development of polyclonal and monoclonal antibodies to the purified F-11 receptor, for use in functional domains of the platelet F-11 antigen, (e) cloning, sequencing and chromosomal localization of the gene for the F-11 receptor. We expect that accomplishment of these research goals will provide new and significant information on basic mechanisms operating during platelet activation. The health-related implications of these studies are particularly relevant to pathophysiological states involving interaction of antibodies with circulating platelets.