ALPHA-1 ANTITRYPSIN AND MACROPHAGE FUNCTION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 α-1-抗胰蛋白酶AAT缺乏症是一种遗传性疾病，在美国影响约100，000人，1-3%的COPD患者。 AAT缺乏可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异常等位基因Pi*Z Glu 324 Lys。 这种Z突变导致AAT蛋白错误折叠和聚合。 多年来，肺气肿的原因被认为仅仅是由于缺乏AAT导致肺实质的蛋白水解破坏。 然而，我们实验室的初步数据表明，具有等位基因的巨噬细胞功能失调，可能导致肺损伤的发展。 我们假设错误折叠的细胞内ZAAT降低了炎症起始的阈值，并损害了巨噬细胞解决炎症的能力。 我们将通过收集外周血单核细胞，肺功能测试，和C-反应蛋白水平正常个人PIMM以及个人与突变等位基因的AAT，PIMZ，皮斯，PIZZ的这一假设进行评估。 使用单核细胞衍生的巨噬细胞，我们将进行几个实验，评估巨噬细胞功能和对AAT缺陷个体与非缺陷对照相比的炎症刺激的反应。 我们还将研究单核细胞成熟为巨噬细胞的各个阶段，以便更好地了解单核细胞-巨噬细胞成熟过程及其对该研究模型的意义。

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 Pi*Z 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.