Role of TIMAP in Vascular Development and Function

TIMAP 在血管发育和功能中的作用

基本信息

批准号：
6891307
负责人：
BARBARA J BALLERMANN
金额：
$ 20.25万
依托单位：
UNIVERSITY OF ALBERTA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-01 至 2006-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by applicant): This project seeks to explore the function of a newly discovered protein, TIMAP, in the development of renal glomerular capillaries and the vasculature in general. We have reported evidence in vitro and in vivo, that TGF-Beta1 signals are necessary for renal glomerular capillary morphogenesis. We now extend our observations to the characterization of a novel TGF-Beta1 responsive gene, and its predicted protein product, which we named TIMAP (TGF-Beta1 inhibited membrane associated protein). In vitro, TIMAP is expressed in endothelial and hematopoietic cells (endothelial and hematopoietic cells are derived from a common lineage), and in vivo TIMAP is expressed predominantly in the vasculature and in renal glomeruli, and TIMAP localizes to endothelial cells and VSMC. We find that TIMAP is the first clearly identified direct intracellular binding partner for the non-integrin 67 kDa laminin receptor (67LR) at the cell membrane. The 67LR is a transmembrane glycoprotein, which interacts specifically and with high affinity with the laminin Beta1 chain. 67LR is a marker for highly motile, metastatic cells in human tumors. In endothelial cells, laminin is required for assembly tubes, and inhibition of the interaction between 67LR and laminin blocks endothelial cell organization into tubes. The 67LR is also required for the upregulation of eNOS in endothelial cells in response to shear stress. To date, the mechanisms whereby signals from the 67LR are transmitted to the cell have not been elucidated. We also find that TIMAP interferes with TGF-Beta1 -stimulated endothelial cell apoptosis, apoptosis being component of TGF-Beta1 stimulated glomerular capillary morphogenesis in vitro. Furthermore, in glomerular capillaries in vivo, TGF-Beta1 is involved in removing superfluous cells through the process of apoptosis, and thereby facilitates capillary lumen formation. The current proposal explores the possibility that TIMAP represents a critical component of a 67LR signaling pathway, and thereby is involved in regulating endothelial cell motility, tube formation, and apoptosis.

描述（由申请人提供）：该项目旨在探索该功能新发现的蛋白质 TIMAP 在肾小球发育中的作用毛细血管和一般脉管系统。我们已经报告了体外证据在体内，TGF-Beta1 信号对于肾小球是必需的毛细血管形态发生。我们现在将观察扩展到表征一种新型 TGF-Beta1 反应基因及其预测的蛋白质产物，我们将其命名为 TIMAP（TGF-Beta1 抑制膜相关蛋白）。体外， TIMAP 在内皮细胞和造血细胞中表达（内皮细胞和造血细胞）造血细胞源自共同谱系），体内 TIMAP 是主要在脉管系统和肾小球中表达，TIMAP 定位于内皮细胞和 VSMC。我们发现TIMAP是第一个明确鉴定出非整合素的直接细胞内结合伴侣 67 细胞膜上的 kDa 层粘连蛋白受体 (67LR)。 67LR是跨膜糖蛋白，与糖蛋白特异性且具有高亲和力地相互作用层粘连蛋白 Beta1 链。 67LR 是高活力、转移性细胞的标记物人类肿瘤。在内皮细胞中，组装管需要层粘连蛋白，并且抑制 67LR 和层粘连蛋白之间的相互作用会阻断内皮细胞组织成管。 67LR 也是 eNOS 上调所必需的内皮细胞对剪切应力的反应。迄今为止，机制来自 67LR 的信号传输至电池时尚未经过阐明了。我们还发现 TIMAP 干扰 TGF-Beta1 刺激的内皮细胞细胞凋亡，细胞凋亡是 TGF-Beta1 刺激的肾小球的组成部分体外毛细血管形态发生。此外，在肾小球毛细血管中在体内，TGF-Beta1 参与去除多余细胞的过程细胞凋亡，从而促进毛细血管腔形成。当前的提案探讨了 TIMAP 代表关键的可能性 67LR 信号通路的组成部分，从而参与调节内皮细胞运动、管形成和细胞凋亡。