Integrin avB8 Inhibits Airway Epithelial Cell Growth

描述(申请人提供)：呼吸道上皮起保护作用 环境和肺实质之间的屏障。吸入的物质是 集中在呼吸道中，使呼吸道上皮易受 烟草致癌物质对人体的伤害和集中作用。正常的 呼吸道的增殖反应通过相互作用受到高度调节 在细胞外信号和化学转化过程中，这种物质的损失 监管最终可能导致肿瘤的发生。细胞整合素家族 表面黏附受体是一个大的分子家族，它可能在 在细胞增殖反应中的中心作用 细胞外基质。在整合素中，α-v亚家族已被证明 在细胞增殖和信号传递中具有特别重要的作用。然而， 整合素在细胞负性调节中的作用知之甚少 扩散。我们的数据表明，αvbeta8整合素在 抑制肺上皮细胞增殖。我们发现， Alphavbeta8仅限于正常的呼吸道上皮细胞，在癌症中缺失。 此外，我们在体外和体内都有证据表明， αvbeta8整合素对肺癌细胞增殖的抑制作用 细胞凋亡。初步数据表明，alphavbeta8通过 两个独立的机制，第一个是通过一种新的机制 直接激活有效的呼吸道上皮细胞抑制因子转化生长因子β 第二种是通过一种涉及抑制信号的新机制 通过Beta8细胞质结构域产生。总而言之，我们的数据 提示alphavbeta8产生负向调节呼吸道的信号 上皮细胞的增殖足以抑制肿瘤 呼吸道表型。拟议的工作解决了以下假设： 整合素αvbeta8对呼吸道上皮细胞和肺癌的负性调节作用 通过两种新的和独立的机制实现细胞增殖，第一种是 包括直接激活转化生长因子β和第二，涉及发散 β8胞质结构域。具体目标：1)检验假设 整合素αvbeta8介导转化生长因子β的激活并通过一种新的 机制；2)检验整合素αvbeta8抑制 通过激活转化生长因子β实现上皮细胞的增殖；3)检测 关于Beta8独特的细胞质结构域调节生长的假说 通过一种独立于转化生长因子β的机制进行抑制。

DESCRIPTION (provided by applicant): Airway epithelium serves as a protective barrier between the environment and the lung parenchyma. Inhaled substances are concentrated in the airways rendering the airway epithelium susceptible to injury and to the concentrated effects of tobacco carcinogens. The normal proliferative responses of the airway are highly regulated through interactions with extracellular cues and during chemical transformation, loss of that regulation may eventually result in neoplasia. The integrin family of cell surface adhesion receptors is a large family of molecules that may play a central role in cellular proliferative responses to cues contained with in the extracellular matrix. Of the integins, the alpha-v subfamily has been shown to be of particular importance in cell proliferation and signaling. However, little is known of the role that integrins play in negative regulation of cell proliferation. Our data suggests that the alphavbeta8 integrin is important in inhibition of lung epithelial proliferation. We find that the expression of alphavbeta8 is confined to normal airway epithelium and is lost in carcinomas. In addition, we have in vitro and in vivo evidence that expression of the alphavbeta8 integrin inhibits lung cancer cell proliferation independent of apoptosis. Preliminary data suggests that alphavbeta8 inhibits growth through two independent mechanisms, the first is mediated through a novel mechanism of direct activation of TGFbeta, a potent inhibitor of airway epithelial cell growth; the second is through a novel mechanism involving inhibitory signals generated through the beta8 cytoplasmic domain. Taken together, our data suggest that alphavbeta8 generates signals that negatively regulate airway epithelial cell proliferation that are sufficient to suppress a neoplastic airway phenotype. The work proposed addresses the following Hypothesis: The integrin alphavbeta8 negatively regulates airway epithelial and lung cancer cell proliferation though two novel and independent mechanisms, the first involving the direct activation of TGFbeta and second, involving the divergent beta8 cytoplasmic domain. Specific Aims: 1) To test the hypothesis that the integrin alphavbeta8 mediates activation of TGFbeta and does so through a novel mechanism; 2) To test the hypothesis that the integrin alphavbeta8 inhibits epithelial cell proliferation through activation of TGFbeta; 3) To test the hypothesis that the unique cytoplasmic domain of beta8 mediates growth inhibition through a mechanism independent of TGFbeta.