ALPHA-1 ANTITRYPSIN AND MACROPHAGE FUNCTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 α-1-抗胰蛋白酶-AAT缺乏症是一种遗传性疾病，在美国约有10万人和1-3%的COPD患者受到影响。AAT缺乏会导致早期肺气肿和肝脏疾病。AAT缺乏症最常见的遗传原因是PIZ异常等位基因Glu324Lys。这种Z突变导致AAT蛋白的错误折叠和聚合。多年来，肺气肿的原因被认为仅仅是由于AAT的缺乏导致了肺实质的蛋白分解破坏。然而，我们实验室的初步数据表明，带有该等位基因的巨噬细胞功能障碍，可能导致肺损伤的发生。我们假设，细胞内错误折叠的Z-AAT降低了炎症启动的阈值，并削弱了巨噬细胞化解炎症的能力。我们将通过收集正常人-PIMM以及AAT、PIMZ、PISZ和PIZ突变等位基因的个体的外周血单核细胞、肺功能测试和C反应蛋白水平来评估这一假设。使用单核细胞来源的巨噬细胞，我们将进行几个实验，评估巨噬细胞的功能和对AAT缺陷个体与非AAT缺陷对照的炎症刺激的反应。我们还将研究单核细胞向巨噬细胞成熟的不同阶段，以更好地了解单核细胞-巨噬细胞成熟过程及其对这一研究模型的意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alpha-1-antitrypsin-AAT deficiency is a hereditary disorder that affects approximately 100,000 individuals in the U.S. and 1-3% of individuals with COPD. AAT deficiency can lead to early emphysema and liver disease. The most common genetic cause of AAT deficiency is the abnormal allele PiZ, Glu324Lys. This Z mutation leads to AAT protein misfolding and polymerization. For years the cause of emphysema was assumed to be due only to the lack of AAT leading to proteolytic destruction of the lung parenchyma. However, preliminary data from our laboratory suggests macrophages with the allele are dysfunctional and may contribute to the development of lung damage. We hypothesize that misfolded intracellular Z AAT lowers the threshold for initiation of inflammation and impairs the ability of macrophages to resolve inflammation. We will evaluate this hypothesis by collecting peripheral blood monocytes, pulmonary function tests, and C-reactive protein levels from normal individuals-PIMM as well as individuals with mutant alleles for AAT, PIMZ, PISZ, and PIZZ. Using monocyte-derived macrophages, we will perform several experiments evaluating macrophage function and response to inflammatory stimuli from AAT deficient individuals compared to non-deficient controls. We will also study various stages of monocyte maturation to macrophages in order to better understand the monocyte-macrophage maturation process and its implication to this model of research.