Genetic Regulation of the Hepatic Acute Phase Response

描述(申请人提供)：组织损伤引发局部 旨在调动急性期反应的炎症反应， 这为生物体提供了一种即时的防御机制。诱导式 生产急性时相蛋白(APP)，如结合珠蛋白(HP)和A1酸 糖蛋白(AGP)与A1的持续高水平表达 -蛋白酶抑制物(A1-PT)是对炎症的关键全身反应。这个 APP在清除有害的炎症产物方面发挥着作用。改型 这些应用程序在小鼠身上的表达表明，它们也有助于 部分通过减少组织损伤反应来消解炎症 由炎性白细胞(特别是中性粒细胞和 单核/巨噬细胞)。假设HP、AGP和A1-PI作为 抗炎药通过调节炎症活性发挥抗炎作用 白细胞。因为肿瘤的生长总是与肿瘤的浸润有关 这样的细胞，也被假设为炎症支持肿瘤细胞 扩散，这种效果受应用程序的调节。在目前的提案中， 这些假说将通过转基因和基因敲除来检验。 老鼠模型。提出了以下目标：(1)确定惠普和 AGP控制中性粒细胞活性，促进抗炎反应 在单核/巨噬细胞中，以及细胞表面是否接受这些APP 在功能上对监管作出贡献；(2)评估 APP在急性时相反应过程中的活性及其对细胞增殖的影响 对体内肿瘤的影响；(3)确定炎症相关效应 蛋白水解酶对A1-PI的切割作用；以及(4)确定A1-PI的作用 卵裂和失活对肿瘤发生的影响。这项研究将定义小说 APP调节炎症过程的机制，并将 加深我们对应用程序如何导致慢性病的理解，例如 癌症。

DESCRIPTION (provided by applicant): Tissue damage initiates a local inflammatory reaction that is designed to mobilize the acute phase response, which provides an immediate defense mechanism for the organism. Induced production of acute phase proteins (APPs), e.g., haptoglobin (HP) and a1-acid glycoprotein (AGP), along with sustained high-level expression of a1 -proteinase inhibitors (a1 -PT) are key systemic reactions to inflammation. The APPs function in the removal of harmful products of inflammation. Modification of expression of these APPs in mice suggest that they also contribute to the resolution of inflammation, in part, by reducing tissue-damaging reactions elicited by inflammatory leukocytes (particularly neutrophils and monocytes/macrophages). It is hypothesized that HP, AGP and a1-PI act as anti-inflammatory agents through modulation of the activities of inflammatory leukocytes. Since tumor growth is invariably associated with infiltration of such cells, it is also hypothesized that inflammation supports tumor cell proliferation, and this effect is regulated by APPs. In the current proposal, these hypotheses will be tested through the use of transgenic and gene knockout mouse models. The following aims are proposed: (1) to determine whether HP and AGP control the activity of neutrophils and promote anti-inflammatory reactions in monocytes/macrophages, and whether the cell surface receptors for these APPs functionally contribute to the regulation; (2) to assess the consequence of the APP activities on the course of acute phase reaction and on the proliferation of tumors in vivo; (3) to identify the effects of inflammation-associated proteinases on the cleavage of a1-PI; and (4) to define the role of a1-PI cleavage and inactivation on tumorigenisis. The study will define novel mechanisms by which the inflammatory process is modulated by APPs, and will deepen our understanding of how APPs contribute to chronic disease, such as cancer.