EMAP II Regulation of Pulmonary Cell Proliferation

描述（由申请人提供）：内皮单核细胞激活多肽（EMAP） II是一种独特的、无领导的单链多肽蛋白，首次从小鼠纤维肉瘤中发现。在其前体形式中，它是34 kda分子，并通过未知机制加工成成熟的21 kda形式。成熟的EMAP II （mEMAP II）是一种细胞外分子，已知可以激活内皮细胞、中性粒细胞和单核吞噬细胞，并且似乎是一种促炎介质，具有启动肿瘤血管进行局部破坏性过程的能力，或者以其自身的能力抗血管生成。我们最近证明，mEMAP II在发育中的肺中是新生血管形成的一个主管，因为它的表达与血管形成的时间呈负相关，并且在小鼠肺发育异体移植模型中引入重组mEMAP II会严重破坏肺泡毛细血管的生长。与细胞外的mEMAP II相比，人们对细胞内形式（pEMAP II）的功能知之甚少。我们的初步数据表明，pEMAP II在分泌之前必须具有重要的细胞内功能，因为：1)其水平与细胞周期密切相关，2)它经历核胞质分配，3)它被翻译后修饰。因此，本提案的具体目的是：1)确定细胞内pEMAP II的亚区隔化和翻译后修饰在细胞周期中的作用；2)确定影响pEMAP II细胞内加工的机制；3)确定EMAP II的分泌机制；4)确定pEMAP II / mEMAP II平衡调节肺生长的细胞外决定因素。因此，确定控制细胞内pEMAP II加工并最终影响其分泌的因素是EMAP II生物学作用的关键决定因素，并将深入了解pEMAP II / mEMAP II平衡影响肺发育的决定因素。

DESCRIPTION (provided by applicant): Endothelial-Monocyte Activating Polypeptide (EMAP) II is a unique, leaderless, single chain polypeptide protein first identified from murine fibrosarcoma. In its precursor form, it is 34-kDa molecule and is processed by unknown mechanisms to a mature 21-kDa form. Mature EMAP II (mEMAP II) is an extracellular molecule that is known to activate endothelial cells, neutrophils and mononuclear phagocytes and appears to be a proinflammatory mediator with the capacity to prime tumor vasculature for a locally destructive process or be anti-angiogenic in its own capacity. We recently demonstrated that mEMAP II is a director of neovascularization in the developing lung as its expression is inversely correlated to periods of vascularization and introduction of recombinant mEMAP II in a murine allograft model of lung development profoundly disrupts alveolar-capillary growth. In contrast to extracellular mEMAP II, considerably less is known regarding the function of the intracellular proform (pEMAP II). Our preliminary data suggest that pEMAP II must have an important intracellular function prior to its secretion because: 1) its levels are tightly regulated in relationship to the cell cycle, 2) it undergoes nucleocytoplasmic partitioning, and 3) it is post-translationally modified. Accordingly, specific alms of this proposal are: 1) To determine the role of intracellular pEMAP II's subcompartmentalization and post-translational modification within the cell cycle; 2) To determine the mechanism that affects intracellular processing of pEMAP II; 3) To determine the mechanism by which EMAP II is secreted; and 4) To identify the extracellular determinants of the pEMAP II / mEMAP II balance in regulating lung growth. Thus, identifying factors that govern the intracellular processing of pEMAP II and ultimately affect its secretion are critical determinants of the biological role of EMAP II and will provide insight into the determinants by which a balance of pEMAP II / mEMAP II can affect lung development.