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ROLE OF CELL SURFACE IN REGULATING CELL PROLIFERATION

细胞表面在调节细胞增殖中的作用

基本信息

批准号：
3227609
负责人：
Darrell H. Carney
金额：
$ 16.19万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-07-01 至 1993-06-30
项目状态：
已结题

项目摘要

The primary objective of this project remains to determine the molecular events that are causally involved in regulating initiation of cell proliferation. These studies are focused on the interaction of thrombin with specific surface receptors on fibroblastic cells and the transmembrane signals elicited by this interaction. We have identified the high-affinity binding domain of thrombin and found it to be homologous to other regulatory molecules including tissue plasminogen activator, suggesting that a family of regulatory molecules may generate their biological signals through interactions with this common receptor. In addition, thrombin binding or interaction with molecules on other cells have been implicated in various aspects of hemostasis and wound healing. Thus, it is more important than ever to determine how thrombin-receptor interaction generates mitogenic signals and how these signals compare with those generated by other thrombin interactions and by growth factors and hormones such as epidermal growth factor (EGF) and insulin. In the proposed studies we will: 1) purify and characterize the high-affinity receptor for thrombin using HPLC and affinity chromatography, examine carbohydrate involvement in thrombin-receptor interaction, sequence a portion of the receptor, construct DNA probes based on this sequence screen genomic and expression libraries and attempt to clone and sequence the gene for the thrombin receptor, 2) characterize signals generated by thrombin enzymic activity an receptor occupancy including phosphoinositide turnover, Ca++ mobilization, diacylglycerol release, protein kinase C activation and specific protein phosphorylation, 3) reconstitute thrombin binding to purified receptors to determine proteolytic and conformational alterations, 4) utilize binding domain synthetic peptides to determine correlations between affinity, size, conformation and signal generation, 5) determine the role of cytoskeletal elements in receptor anchorage and transmembrane signalling and 6) identify and purify other regulatory molecules which interact with thrombin receptors to help evaluate the utility of this receptor system in various tissues and different cellular functions.

该项目的主要目标仍然是确定与调控有关的分子事件启动细胞增殖。这些研究主要集中在凝血酶与血管内皮细胞表面受体的相互作用成纤维细胞及其引发的跨膜信号互动。我们已经鉴定了高亲和力结合结构域发现它与其他调节因子同源包括组织纤溶酶原激活剂在内的分子，表明一系列调节分子可能会产生它们的生物学特性通过与这种共同受体的相互作用来传递信号。在……里面此外，凝血酶与其他分子的结合或相互作用细胞与止血的各个方面有关，而且伤口愈合。因此，比以往任何时候都更重要的是确定凝血酶-受体相互作用如何产生有丝分裂信号以及这些信号与其他设备产生的信号相比如何凝血酶相互作用以及生长因子和激素，如表皮生长因子和胰岛素。在建议的研究内容：1)纯化和鉴定高亲和力凝血酶受体的高效液相色谱和亲和层析，检测碳水化合物与凝血酶受体的关系相互作用，对一部分受体进行测序，构建DNA 基于该序列的探针筛选基因组和表达文库，并尝试克隆和测序该基因凝血酶受体，2)表征凝血酶产生的信号酶活性和受体占有率包括肌醇磷脂周转、钙离子动员、甘油二酯释放、蛋白激酶C激活和特定蛋白磷酸化，3)重建凝血酶与纯化的结合决定蛋白质降解和构象的受体改变，4)利用结合结构域合成肽确定亲和力、大小、构象和信号产生，5)决定细胞骨架元素的作用受体锚定和跨膜信号和6) 鉴定和纯化与之相互作用的其他调节分子凝血酶受体有助于评估该受体的效用系统在不同的组织和不同的细胞功能。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glycosylation of high-affinity thrombin receptors appears necessary for thrombin binding.

高亲和力凝血酶受体的糖基化似乎是凝血酶结合所必需的。

DOI：
10.1016/s0006-291x(05)81299-9
发表时间：
1991
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Frost,GH;Bergmann,JS;Carney,DH
通讯作者：
Carney,DH

Acceleration of full-thickness wound healing in normal rats by the synthetic thrombin peptide, TP508.

合成凝血酶肽 TP508 加速正常大鼠全层伤口愈合。

DOI：
10.1046/j.1524-475x.2000.00204.x
发表时间：
2000
期刊：
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
影响因子：
0
作者：
Stiernberg,J;Norfleet,AM;Redin,WR;Warner,WS;Fritz,RR;Carney,DH
通讯作者：
Carney,DH

Mouse fibroblasts defective in thrombin mitogenesis possess functional proteolytically activated receptor for thrombin: requirement for a second signaling pathway.

凝血酶有丝分裂发生缺陷的小鼠成纤维细胞具有功能性蛋白水解激活凝血酶受体：需要第二条信号通路。