Role of JAM Family in Angiogenesis

血管的发育和完整性受一系列信号事件的调控， 通过内在和外在的线索。这些研究的长期目标是确定身份， 基因的功能，参与血管发育的过程，并检查如何异常 功能会导致血管疾病。为了发生血管生成，静息内皮细胞（EC）需要 被激活，从相对静止的状态中走出来，并启动信号级联， 增殖、ECM降解和细胞迁移。越来越多的生长因子和细胞因子 如bFGF、VEGF和TNF-α促进血管生成。尽管不同的血管生成因子 刺激最初不同的信号传导途径，它们激活共同的下游事件， MAP激酶导致新血管形成所必需的几种基因产物的转录激活 阵细胞表面分子如整合素和CAM已被证明参与了这一过程。 然而，关于整合素在血管生成中的重要作用，存在相互矛盾的数据。 我们最近的研究表明，IG超家族成员之一的连接粘附分子-A（Junctional Adhesion Molecule-A，JAM-A）是一个关键的免疫调节因子， bFGF诱导的血管生成的调节剂。然而，JAM-A调节这一点的机制 产品未被阐明。该提案旨在研究通过以下途径调节血管生成的机制： JAM-A和其他JAM家族成员在以下三个具体方面对这一进程的贡献 目标。1)将研究JAM-A对生长因子诱导的血管生成的调节机制。 通过使用EC体外和使用JAM-A缺失小鼠体内。2)细胞内信号传导途径 JAM-A将通过鉴定可能与JAM-A相关的信号蛋白和通过解剖JAM-A的细胞来研究。 下游信号事件使用特定的抑制剂。3)JAM家族成员之间的串扰，JAM-A， 将使用敲除动物在体外和体内研究JAM-B和JAM-C。这次调查 有可能增加我们对导致心血管疾病的血管疾病的理解 和中风此外，阐明了JAM-A在内皮细胞增殖和迁移中的作用，从而导致细胞凋亡。 血管生成将为肿瘤发生和血管生物学的研究开辟一条新的途径。

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.