INFLAMMATION IN THE PATHOGENESIS OF COPD

描述（改编自申请人的摘要） 研究人员的建议的目标是确定产品的作用， 位于人类染色体19p13.3-pter上的基因的表达在 慢性阻塞性肺病 这个基因座含有三个协同表达的基因， 嗜中性粒细胞衍生的丝氨酸蛋白酶同系物，嗜中性粒细胞弹性蛋白酶（NE）， 蛋白酶-3（PR-3）和杀天青素（AZU）。 该基因簇的产物代表多功能炎症反应 具有不同但重叠功能的调解人不仅涉及 在基质破坏中，但也提供了产生 促炎细胞因子、淋巴细胞和单核细胞募集以及凋亡。 第一个具体目标将确定19p13.3-pter丝氨酸 蛋白酶同系物在体外作为促炎介质发挥作用。 的 第二个具体目标将建立模型的损失或增益的功能， 19p13.3-pter丝氨酸蛋白酶同源物通过体内遗传操作。 第三个具体目标将决定改变基因的后果 19p13.3-pter丝氨酸蛋白酶同系物在炎症中的表达， 组织破坏和气流受限。 研究人员的第一个具体目标的策略将是包容性的 测定19p13.3-pter同系物诱导合成的能力， 肺细胞释放促炎细胞因子。 第二部分 aim将追踪最近的观察，即激活的淋巴细胞合成 19p13.3-pter蛋白酶，从而扩展了蛋白酶的发病机制 假设包括淋巴细胞的作用。 第二个具体目标将 开发19p13.3-pter丝氨酸蛋白酶同源物功能丧失的模型 通过在小鼠中使用同源重组产生靶向缺失。 增益 通过靶向表达这些基因， 使用骨髓特异性启动子的骨髓细胞。 第三个具体目标是 确定19p13.3-pter基因表达改变的后果 丝氨酸蛋白酶同系物对香烟烟雾中COPD发展的影响 暴露的老鼠 这项工作将为19p13.3-pter丝氨酸的作用提供新的见解 蛋白酶同系物在肺部健康和疾病，特别是在 COPD的发病机制。 结果将有助于确定肺的关系 炎症和组织破坏导致气流受限和过度充气 在COPD患者中。

DESCRIPTION (adapted from the applicants' abstract) The goal of the investigators' proposal is to determine the role that products of genes located on human chromosome 19p13.3-pter play in the pathogenesis of COPD. This locus contains the genes for three coordinately expressed neutrophil-derived serine proteinase homologues, neutrophil elastase (NE), proteinase-3 (PR-3) and azurocidin (AZU). The products of this gene cluster represent multi-functional inflammatory mediators with distinct but overlapping functions that are involved not only in matrix destruction, but that also provide signals for production of proinflammatory cytokines, lymphocyte and monocyte recruitment, and apoptosis. The first specific aim will determine the ability of the 19p13.3-pter serine proteinase homologues to function as proinflammatory mediators in vitro. The second specific aim will create models of loss or gain of function of the 19p13.3-pter serine proteinase homologues by genetic manipulation in vivo. The third specific aim will determine the consequences of altered gene expression of the 19p13.3-pter serine proteinase homologues on inflammation, tissue destruction and airflow limitation in COPD. The investigators' strategy for the first specific aim will be to inclusively determine the ability the 19p13.3-pter homologues to induce synthesis and release of proinflammatory cytokines by lung cells. The second part of this aim will pursue recent observations that activated lymphocytes synthesize the 19p13.3-pter proteinases, thus extending the proteinase pathogenesis hypothesis to include a role for lymphocytes. The second specific aim will develop models of 19p13.3-pter serine proteinase homologue(s) loss of function by creating targeted deletions using homologous recombination in mice. Gain of function models will be developed by targeting expression of these genes to myeloid cells using myeloid specific promoters. The third specific aim will determine the consequences of altered gene expression of the 19p13.3-pter serine proteinase homologues on the development of COPD in cigarette smoke- exposed mice. This work will provide new insights into the role of the 19p13.3-pter serine proteinase homologues in lung health and disease, particularly in the pathogenesis of COPD. The results will help define the relationships of lung inflammation and tissue destruction to airflow limitation and hyperinflation in COPD sufferers.