Genetic Regulation of the Hepatic Acute Phase Response

肝脏急性期反应的基因调控

• 批准号: 6693745
• 负责人: HEINZ BAUMANN
• 金额: $ 37.45万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693745
• 关键词: acute phase protein; alpha 1 acid glycoprotein; antiinflammatory agents; carcinogenesis; gene induction /repression; genetically modified animals; haptoglobins; human tissue; immunogenetics; inflammation; laboratory mouse; liver metabolism; protease inhibitor; protein structure function; tissue /cell culture; transcription factor; transfection /expression vector

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.

描述（由申请人提供）：组织损伤引发局部 旨在动员急性期反应的炎症反应， 这为生物体提供了直接防御机制。诱导 产生急性期蛋白（APP），例如，结合珠蛋白和α 1-酸 糖蛋白（AGP），沿着持续高水平表达a1 α 1-蛋白酶抑制剂（α 1-PT）是炎症的关键全身反应。的 APP的功能是清除炎症的有害产物。修改 这些APP在小鼠中的表达表明，它们也有助于 通过减少组织损伤反应，部分缓解炎症 由炎性白细胞（特别是嗜中性粒细胞， 单核细胞/巨噬细胞）。假设HP、AGP和α 1-PI作为 通过调节炎性细胞因子活性的抗炎剂 白细胞由于肿瘤的生长总是与肿瘤细胞的浸润有关， 这种细胞，也假设炎症支持肿瘤细胞 增殖，这种作用是由APPs调节的。在目前的提案中， 这些假设将通过使用转基因和基因敲除来检验。 小鼠模型。提出了以下目标：（1）确定HP和 AGP控制中性粒细胞活性，促进抗炎反应 在单核细胞/巨噬细胞中，以及这些APP的细胞表面受体 （2）在法律规定的范围内，对当事人的权利义务进行限制。 APP活性在急性期反应过程中的变化及对细胞增殖的影响 （3）确定炎症相关性的影响， 蛋白酶对α 1-PI裂解的影响;（4）确定α 1-PI的作用 裂解和失活对肿瘤发生的影响。该研究将定义小说 炎症过程由APP调节的机制， 加深我们对APP如何促进慢性病的理解，例如 癌