Integrin avB8 Inhibits Airway Epithelial Cell Growth

描述（由申请人提供）：气道上皮细胞作为保护性 环境和肺实质之间的屏障。吸入的物质是 集中在气道中，使得气道上皮对 伤害和烟草致癌物的集中影响。正常 气道的增殖反应通过相互作用高度调节 在化学转化过程中， 调节可能最终导致瘤形成。细胞整合素家族 表面粘附受体是一个大家族的分子， 在细胞增殖反应中的核心作用， 细胞外基质在整合素中，已显示α-v亚家族 在细胞增殖和信号传导中特别重要。然而，在这方面， 整合素在细胞负调控中的作用知之甚少 增殖我们的数据表明，α v β 8整合素在 抑制肺上皮细胞增殖。我们发现， α v β 8局限于正常气道上皮，并在癌中丢失。 此外，我们有体外和体内的证据表明， α v β 8整联蛋白抑制肺癌细胞增殖 凋亡初步数据表明，alphavbeta 8通过以下途径抑制生长： 两种独立的机制，第一种是通过一种新的机制介导的， 直接激活TGF β，一种有效的气道上皮细胞抑制剂 第二种是通过一种涉及抑制信号的新机制 通过β 8胞质结构域产生。综合来看，我们的数据 表明α v β 8产生负调节气道的信号 足以抑制肿瘤的上皮细胞增殖 气道表型所提出的工作解决了以下假设： 整合素α v β 8负调节气道上皮和肺癌 细胞增殖通过两个新的和独立的机制，第一 包括TGF β的直接激活，第二，包括趋化因子的分化， β 8胞质结构域。具体目的：1）检验假设， 整合素α v β 8介导TGF β的活化，并通过一种新的 2）检验整合素α v β 8抑制 通过活化TGF β的上皮细胞增殖; 3）为了测试 β 8的独特胞质结构域介导生长的假说 通过独立于TGF β的机制抑制。

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.