Alcohol and Liver Endothelial Cells in Immune Responses

描述(申请人提供)：肝窦内皮细胞(SECs)的主要功能是通过其所谓的“清道夫”功能进行宿主防御和动态平衡，从而识别、内化和降解各种细胞外基质成分和修饰蛋白。事实上，我们实验室最近的报告表明，多种乙醛修饰的蛋白质可以被SECS去除，包括最近描述的丙二醛-乙醛加合物(MAA)。初步数据表明，一系列受体，通常被称为清道夫受体，似乎在MAA修饰的蛋白质反应中介导SECs的生物学功能。在正常情况下，MAA修饰的蛋白质与Secs上的清道夫受体结合并被降解。然而，在长期饮用乙醇之后，研究表明，这些加合物的降解率下降了50%-60%。因此，我们假设在慢性酒精摄入后，MAA修饰的肝细胞蛋白被释放到周围组织中。结合这些MAA修饰蛋白的受体(S)根据细胞激活水平、结合的受体数量、结合的受体类型以及SECs的反应能力而改变。这导致了促炎和促纤维化反应的刺激，这可能在酒精性肝病(ALD)的发生和/或进展中发挥重要作用。因此，本研究项目的主要目的是更好地定义和鉴定负责MAA修饰蛋白结合的SECs上的受体(S)，并确定慢性酒精摄入对其正常生物学功能的影响。初步研究将开始利用分子和免疫学技术描绘与MAA修饰蛋白结合的受体。进一步的体外研究将试图确定SECs通过已识别的清道夫受体激活以产生促炎和促纤维化反应的机制(S)。最后，将启动研究以评估MAA修饰的蛋白质与不同受体在SEC上结合的影响，并导致抗原驱动的免疫反应的启动。因此，这些研究将继续研究SECS、MAA修饰的蛋白质和慢性酒精摄入在ALD炎症和纤维化反应的发展和/或进展中的作用。

DESCRIPTION (provided by applicant): The major function of liver sinusoidal endothelial cells (SECs) is in host defense and homeostasis via their so-called "scavenger" function whereby they recognize, internalize and degrade a variety of extracellular matrix components and modified proteins. In fact, recent reports from our laboratory have shown that a variety of aldehyde modified proteins are removed by SECs, including the recently described malondialdehyde-acetaldehyde adduct (MAA). Preliminary data have demonstrated that a family of receptors, commonly known as scavenger receptors, appears to mediate the biological functions of SECs in response to MAA-modified proteins. Under normal conditions, MAA-modified proteins bind to scavenger receptors on SECs and are degraded. However, following chronic ethanol consumption, it has been shown that there is a 50-60% decrease in the degradation of these adducts. Thus, we hypothesize that following chronic ethanol consumption, MAA-modified hepatocyte proteins are released into the surrounding tissues. The receptor(s) that bind these MAA-modified proteins are altered with respect to the level of cell activation, the number of receptors bound, the types of receptors bound, and the ability of the SECs to respond. This results in the stimulation of pro-inflammatory and pro-fibrotic responses that may play a prominent role in the development and/or progression of alcoholic liver disease (ALD). Therefore, the principal objective of this research project is to better define and characterize the receptor(s) on SECs responsible for the binding of MAA modified proteins, and determine the effects of chronic ethanol consumption on their normal biological functions. Initial studies will begin to delineate the receptors that bind MAA modified proteins using molecular and immunological techniques. Further in vitro studies will attempt to determine the mechanism(s) by which SECs are activated through the identified scavenger receptors to produce pro-inflammatory and pro-fibrotic responses. Finally, studies will be initiated to assess the effects of the binding of MAA-modified proteins to different receptors on SECs and result in the initiation of antigen-driven immune responses. Thus, these studies will continue to investigate the role of SECs, MAA-modified proteins, and chronic ethanol consumption in the development and/or progression of the inflammatory and fibrotic responses observed in ALD.