Alcohol and Liver Endothelial Cells in Immune Responses

描述（由申请人提供）：肝窦内皮细胞（SEC）的主要功能是通过其所谓的“清道夫”功能进行宿主防御和体内平衡，由此它们识别、内化和降解各种细胞外基质组分和修饰的蛋白质。事实上，我们实验室最近的报告表明，各种醛修饰的蛋白质被SEC去除，包括最近描述的丙二醛-乙醛加合物（MAA）。初步数据表明，一个家族的受体，通常被称为清道夫受体，似乎介导响应MAA修饰的蛋白质的SEC的生物学功能。在正常条件下，MAA修饰的蛋白质与SEC上的清道夫受体结合并被降解。然而，在长期消耗乙醇之后，已经表明这些加合物的降解减少了50-60%。因此，我们假设，慢性乙醇消耗后，MAA修饰的肝细胞蛋白被释放到周围组织中。结合这些MAA修饰的蛋白质的受体在细胞活化水平、结合的受体数量、结合的受体类型和SEC应答能力方面发生改变。这导致促炎和促纤维化反应的刺激，这可能在酒精性肝病（ALD）的发展和/或进展中起重要作用。因此，本研究项目的主要目标是更好地定义和表征负责MAA修饰蛋白结合的SEC上的受体，并确定慢性乙醇消耗对其正常生物学功能的影响。初步研究将开始，以描绘受体结合MAA修饰的蛋白质，使用分子和免疫学技术。进一步的体外研究将试图确定SEC通过鉴定的清道夫受体活化以产生促炎和促纤维化反应的机制。最后，将启动研究以评估MAA修饰的蛋白质与SEC上不同受体的结合的影响，并导致抗原驱动的免疫应答的启动。因此，这些研究将继续研究SEC、MAA修饰的蛋白质和慢性乙醇消耗在ALD中观察到的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.