APOPTOSIS-RELATED GENETIC POLYMORPHISMS IN SARCOIDOSIS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。肉芽肿是身体的白色血细胞，包括淋巴细胞和巨噬细胞的有组织的聚集。肺部肉芽肿的形成是对感染因子、异物和未知原因的反应。结节病是一种病因不明的慢性肉芽肿性肺病。促进最终导致这种疾病过程的炎症反应的机制还不清楚。在某些家庭和特定种族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。有遗传背景的个体更容易发生肉芽肿，更容易发生结节病。我们的研究试图描述肉芽肿形成的可能机制，将在此过程中可能重要的蛋白质与可能增加结节病易感性的基因联系起来。其中一组基因可能与细胞凋亡或程序性细胞死亡有关。细胞凋亡可以通过死亡受体与死亡配体的结合来启动。一些研究发现细胞凋亡在肉芽肿性疾病，包括结节病。实验数据表明肉芽肿诱导剂也可诱导细胞凋亡。在结节病中，Fas（CD 95，Apo-1）和肿瘤坏死因子（TNF，TNF-α，cachectin）两种凋亡蛋白表达增高，提示细胞凋亡可能在肉芽肿性炎症的发生发展中起重要作用。 本研究探讨这两个凋亡基因的遗传差异是否可能导致较高的蛋白水平和凋亡，甚至增加结节病的易感性。此外，如果细胞凋亡在这种炎症过程的发展中很重要，它可能导致更严重的疾病。在这项研究中，我们计划评估与健康对照相比，结节病患者的Fas和TNF表达水平，并确定这些较高的水平是否与较高的细胞凋亡水平有关。我们还将评估结节病患者是否更可能携带Fas和TNF基因的特定变体，这可能与Fas和TNF的蛋白质和基因水平较高相关。最后，我们将确定这些遗传变异是否与结节病中更严重的疾病过程相关。这些信息将帮助我们确定遗传易感性因素，这些因素可能使某些个体易患结节病和可能更严重的疾病，以及可能发生的方式。

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.