APOPTOSIS-RELATED GENETIC POLYMORPHISMS IN SARCOIDOSIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。肉芽肿是人体内包括淋巴细胞和巨噬细胞在内的白细胞的有组织的聚集体。肺肉芽肿是对感染物、异物和不明原因的反应而形成的。结节病是一种原因不明的慢性肉芽肿性肺部疾病。促进炎症反应，最终导致这种疾病过程的机制还不是很清楚。在一些家庭和特定族裔群体中观察到结节病的高发病率，提出了这种疾病的遗传基础的问题。具有易患肉芽肿的遗传背景的人很可能更容易患上结节病。我们的研究试图描述肉芽肿形成的可能机制，将在这一过程中潜在重要的蛋白质与可能增加结节病易感性的基因联系起来。可能牵涉到的一组基因是那些参与细胞凋亡或程序性细胞死亡的基因。细胞凋亡可以通过死亡受体与死亡配体的结合来启动。一些研究发现，包括结节病在内的肉芽肿性疾病中存在细胞凋亡。初步数据表明，肉芽肿诱导剂也可能诱导细胞凋亡。在结节病中，Fas(CD95，Apo-1)和肿瘤坏死因子(TNF，TNF-a，cachectin)两种凋亡蛋白水平较高。细胞凋亡可能在肉芽肿性炎症的发生发展中起重要作用。我们的研究质疑这两个凋亡基因的遗传差异是否会导致更高的蛋白水平和细胞凋亡，甚至增加结节病的易感性。此外，如果细胞凋亡在炎症过程的发展中很重要，它可能会导致更严重的疾病。在这项研究中，我们计划评估结节病患者与健康对照组相比Fas和TNF的表达水平，并确定这些更高的水平是否与更高的细胞凋亡水平有关。我们还将评估这些结节病患者是否更有可能携带Fas和TNF基因的特定变体，这可能与Fas和TNF的蛋白和基因水平较高有关。最后，我们将确定这些基因变异是否与结节病的更严重的疾病过程有关。这些信息将帮助我们确定遗传易感因素，这些因素可能使一些人倾向于发展成结节病，并可能发生更严重的疾病，以及可能发生这种情况的方法。

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. Granulomas are organized aggregations of the body's white blood cells, including lymphocytes and macrophages. Lung granulomas form in response to infectious agents, foreign materials and for unknown reasons. Sarcoidosis is a chronic granulomatous lung disease without a known cause. The mechanisms which promote the inflammatory response which eventually result in this disease process are not well understood. Observations of high rates of sarcoidosis in some families and specific ethnic groups has raised the question of a genetic basis for this disease. It is likely that individuals with a genetic background which predispose them to developing granulomas are more likely to develop sarcoidosis. Our study seeks to describe a possible mechanism by which granulomas may form, linking proteins potentially important in this process to genes which might increase susceptibilty to sarcoidosis. One set of genes that may be implicated are those involved in apoptosis, or programmed cell death. Apoptosis may be initiated by binding of a death receptor to a death ligand. A few studies have found apoptosis in granulomatous diseases, including sarcoidosis. Prelimanary data suggest that granuloma-inducing agents may also induce cell apoptosis. In sarcoidosis, high levels of two apoptosis proteins, Fas (CD95, Apo-1) and tumor necrosis factor (TNF, TNF-a, cachectin), are found. It is possible that apoptosis is important in the development of granulomatous inflammation. Our study quesions whether genetic differences in these two apoptosis genes might result in higher protein levels and apoptosis, and even increased susceptibility to sarcoidosis. Furthermore, if apoptosis is important in the development of this inflammatory process, it may result in more severe disease. In this study, we plan to evaluate the levels of Fas and TNF expression in individuals with sarcoidosis compared to healthy controls and determine whether these higher levels are associated with higher levels of apoptosis. We also will evaluate whether those subjects with sarcoidosis are more likely to carry specific variants of the Fas and TNF genes, which may be associated with higher protein and gene levels of Fas and TNF. Finally, we will determine whether these genetic variants are associated with a more severe disease process in sarcoidosis. This information will help us define genetic susceptibility factors which may predispose some individuals to the development of sarcoidosis and possibly more severe disease and a means by which this may occur.