Modulation of Host Cell Exosome Content and Function by EBV LMP1

 描述（由申请人提供）：外泌体是从癌细胞中高水平释放的小囊泡，是肿瘤环境的重要调节剂，并有助于疾病进展。外泌体含有关于其来源细胞的分子信息，并且可以从许多生物流体（包括血液、尿液和唾液）中分离。最近发现，来自乳腺癌细胞或该疾病患者血液的外泌体可导致非癌细胞形成肿瘤。这些发现表明外泌体在癌症发展或疾病进展中的关键作用，并为基于外泌体的诊断和治疗创造了新的机会。根据我们的研究和其他研究的数据，也越来越清楚的是，致癌病毒利用和修改宿主细胞外泌体途径，这些变化可能导致疾病。例如，感染EB病毒（EBV）（一种人类肿瘤病毒）的细胞释放富含病毒产物（如主要病毒致癌基因潜伏膜蛋白1（LMP 1）和病毒编码的miRNA）的外泌体。我们之前已经表明，LMP 1改变了从感染细胞释放的外泌体的货物，并且这些LMP 1修饰的外泌体可以对邻近的未感染细胞发挥致癌信号传导功能。尽管LMP 1修饰的外泌体的细胞间传递的重要性，但关于这种病毒蛋白实际上如何进入并操纵宿主外泌体途径的知之甚少。这些研究的总体目标是确定LMP 1驱动外泌体内容重组和改变外泌体功能的机制。我们假设LMP 1外泌体的运输通过改变内吞途径和膜微区来调节外泌体的组分和生物学特性。为了测试这一点，我们的目标是：1。研究LMP 1改变外泌体组分的机制; 2.）确定LMP 1修饰的外泌体在细胞内通讯和细胞转化中的功能。

 DESCRIPTION (provided by applicant): Exosomes are small vesicles released at high levels from cancer cells that are important modifiers of the tumor environment and contribute to disease progression. Exosomes contain molecular information about their cells of origin and can be isolated from many biological fluids including blood, urine, and saliva. It has recently been discovered that exosomes from breast cancer cells or the blood of patients with the disease can cause non- cancerous cells to form tumors. These findings suggest a critical role of exosomes in cancer development or disease progression, and create new opportunities for exosome-based diagnostics and therapies. Based on data from our studies and others, it is also becoming clear that cancer causing viruses utilize and modify the host cell exosome pathway, and these changes may contribute to disease. For example, cells infected with the Epstein-Barr virus (EBV), a human tumor virus, release exosomes that are enriched in viral products like the major viral oncogene latent membrane protein 1 (LMP1) and virally-encoded miRNAs. We have previously shown that LMP1 alters the cargo of exosomes released from infected cells and that these LMP1-modifed exosomes can exert oncogenic signaling functions on neighboring uninfected cells. In spite of the importance of inter-cellular transmission of LMP1-modifeid exosomes, very little is known about how this viral protein actually enters and manipulates the host exosome pathway. The overall goal of these studies is to determine the mechanisms that LMP1 drives exosome content reorganization and alters the functions of exosomes. We hypothesize that LMP1 exosomal trafficking modulates the components and biological properties of exosomes by altering endocytic routes and membrane microdomains. To test this, we aim to: 1.) investigate the mechanism through which LMP1 alters exosome components; 2.) determine the functions of LMP1-modified exosomes in intracellular communication and cellular transformation.