Structure And Function Of Phagocyte Proteins

中性粒细胞和其他循环吞噬细胞产生高水平的活性氧（ROS），以响应各种感染或炎症刺激，这一过程称为呼吸爆发。这种反应归因于NADPH氧化酶的活性，NADPH氧化酶产生超氧化物，超氧化物是ROS的前体，ROS是重要的杀微生物剂和炎症介质。患有慢性肉芽肿病（CGD）的患者具有NADPH氧化酶缺陷，并且遭受对微生物感染和异常炎症反应的增强的易感性。该项目探索调节吞噬细胞呼吸爆发的细胞机制，并表征各种非免疫细胞中表达的相关酶的氧化反应。 在旨在定义触发吞噬细胞氧化酶（phox）激活的信号转导途径的工作中，我们采用基因转染方法来证明小GTdR、ADP-核糖基化因子-6（ARF-6）和磷脂酶D参与呼吸爆发。影响吞噬细胞呼吸爆发的信号传导中间体的信息将为旨在抑制或增强吞噬细胞氧化反应的治疗策略（药理学靶点）提供基础。在其他研究中，我们正在表征其他组织（脑、血管组织、结肠、肾、甲状腺和唾液腺）中活性氧的来源。在这些部位，氧化剂可用于宿主防御或炎症反应或提供影响基因表达模式的氧化还原“第二信使”（对生长因子的增殖反应、分化、细胞衰老、凋亡或程序性细胞死亡、氧传感）。在CGD的p47 phox缺陷小鼠模型中的研究表明，p47 phox在响应于中性粒细胞激动剂或淀粉样蛋白-β的小胶质细胞释放反应性氧化剂中起重要作用，这可能与阿尔茨海默病相关的神经退行性过程有关。主动脉平滑肌细胞对PDGF或血管紧张素II的正常氧化反应在p47 phox缺陷小鼠中也不存在，表明血管组织中涉及吞噬细胞样氧化酶。最后，目前正在开发改变氧化酶组分（Nox 4、Nox 1和p22 phox）的转基因小鼠模型（基因“敲除”和条件性反义“敲低”），以探索这些系统在健康和疾病中的作用。

Neutrophils and other circulating phagocytes generate high levels of reactive oxygen species (ROS) in response to a variety of infectious or inflammatory stimuli in a process known as the respiratory burst. This response is attributed to the activity of NADPH oxidase, which produces superoxide, a precursor of ROS that are important microbicidal agents and mediators of inflammation. Patients with chronic granulomatous disease (CGD) have NADPH oxidase deficiencies and suffer from enhanced susceptibility to microbial infections and aberrant inflammatory responses. This project explores the cellular mechanisms regulating the respiratory burst in phagocytes and is characterizing oxidative responses of related enzymes expressed in a variety of non-immune cells. In work aimed at defining signal transduction pathways triggering activation of the phagocyte oxidase (phox), we have engaged gene transfection approaches to demonstrate involvement of the small GTPase, ADP-ribosylation factor-6 (ARF-6), and phospholipase D in the respiratory burst. Information on signaling intermediates affecting the respiratory burst in phagocytes will provide a basis for therapeutic strategies (pharmacological targets) designed to inhibit or enhance oxidative responses of phagocytes. In other studies we are characterizing sources of reactive oxygen species in other tissues (brain, vascular tissue, colon, kidney, thyroid and salivary glands). In these sites, the oxidants may serve in host defense or inflammatory reactions or provide redox "second messengers" that affect gene expression patterns (proliferation responses to growth factors, differentiation, cellular senescence, apoptosis or programmed cell death, oxygen sensing). Studies in the p47phox-deficient mouse model of CGD indicate an essential role for p47phox in the release of reactive oxidants by microgial cells in response to neutrophil agonists or amyloid-beta, which may relate to neurodegenerative processes associated with Alzheimer's disease. The normal oxidative responses of aortic smooth muscle cells to PDGF or angiotensin II are also absent in p47phox-deficient mice, indicating involvement of a phagocyte-like oxidase in vascular tissue. Finally, transgenic mouse models (gene "knock-out" and conditional antisense "knock-down") in which oxidase components (Nox 4, Nox 1 and p22phox) are altered are currently under development to explore the roles of these systems in health and disease.