Role of JAM Family in Angiogenesis

血管的发育和完整性受触发的一系列信号事件的调节 既有内在的也有外在的。这些研究的长期目标是确定身份和 参与血管发育过程的基因的功能，并检查异常情况 功能障碍可能会导致血管紊乱。为了发生血管生成，静止的内皮细胞(ECs)需要 被激活以摆脱其相对静止状态并启动信号级联，从而导致 促进细胞增殖、细胞外基质降解和细胞迁移。越来越多的生长因子和细胞因子 如碱性成纤维细胞生长因子、血管内皮生长因子、肿瘤坏死因子-α等促进血管生成。虽然，不同的血管生成因子 刺激最初不同的信号通路它们激活共同的下游事件，如激活 MAP激酶导致新血管所必需的几种基因产物的转录激活 队形。细胞表面分子，如整合素和细胞黏附分子，已被证明与此有关。 然而，关于整合素在血管生成中的重要作用，一直存在相互矛盾的数据。 我们最近发现，连接黏附分子-A，JAM-A，Ig超家族的成员之一，是一个关键 碱性成纤维细胞生长因子诱导的血管生成调节因子。然而，JAM-A调节这一点的机制 产品未予说明。该提案旨在研究通过以下方式调节血管生成的机制 Jam-A和Jam家族的其他成员在这一过程中的贡献具体有以下三个 目标。1)JAM-A对生长因子诱导的血管生成的调节机制将在 体外使用内皮细胞，体内使用JAM-A基因缺失小鼠。2)细胞内信号转导途径 JAM-A将通过鉴定可能与JAM-A相关的信号蛋白和通过解剖 使用特定抑制剂的下游信号事件。3)JAM家庭成员之间的串扰，JAM-A， JAM-B和JAM-C将在体外和体内使用基因敲除动物进行研究。这项调查 有可能增加我们对导致心血管疾病的血管紊乱的了解 还有中风。进一步，阐明JAM-A在内皮细胞增殖和迁移中的作用导致 血管生成将开辟一条在肿瘤发生和血管生物学中具有重要意义的新研究方向。

The development and integrity of blood vessels are regulated by cascade of signaling events triggered by both intrinsic and extrinsic cues. The long term goal of these studies is to determine the identity and function of the genes that are involved in the process of vascular development and to examine how aberrant functions can lead to vascular disorders. For angiogenesis to occur, resting endothelial cells (ECs) need to be activated to emerge out of their relative state of quiescence and to initiate signaling cascade that will lead to proliferation, ECM degradation and cell migration. A growing number of growth factors and cytokines such as bFGF, VEGF and TNF-alpha promote angiogenesis. Although, different angiogenic factors stimulate initially distinct signaling pathways they activate common downstream events such as activation of MAP kinases leading to transcriptional activation of several gene products necessary for new blood vessel formation. Cell surface molecules such as integrins and CAMs have been shown to be involved in this process however, there has been conflicting data regarding the essential role of integrins in angiogenesis. We have recently shown that Junctional Adhesion Molecule-A, JAM-A, a member of Ig superfamily is a key regulator of angiogenesis induced by bFGF. However, the mechanism by which JAM-A regulates this product is not elucidated. The proposal seeks to investigate the mechanism of regulation of angiogenesis by JAM-A and the contribution of the other JAM family members in this process in the following three specific aims. 1) Mechanism of regulation of growth factor-induced angiogenesis by JAM-A will be investigated in vitro by using ECs and in vivo using JAM-A null mice. 2) Intracellular signaling pathway induced through JAM-A will be studied by identifying signaling proteins that may associate with JAM-A and by dissecting the downstream signaling events using specific inhibitors. 3) Cross talk between JAM family members, JAM-A, JAM-B and JAM-C will be investigated both in vitro and in vivo using knockout animals. This investigation has the potential to increase our understanding of vascular disorders that lead to cardiovascular diseases and stroke. Further, elucidation of the role of JAM-A in endothelial cell proliferation and migration leading to angiogenesis will open up a mew line of investigation that is important in tumerigenesis and vascular biology.