Parameters Governing Kidney Cell Infection with BKV

BKV 肾细胞感染的控制参数

• 批准号: 6803768
• 负责人: MICHAEL J. IMPERIALE
• 金额: $ 30.17万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803768
• 关键词: Polyomavirus; clinical research; cytokine; gene expression; histology; host organism interaction; human tissue; kidney cell; life cycle; microarray technology; molecular cloning; northern blottings; polymerase chain reaction; tissue /cell culture; virus genetics; virus infection mechanism

DESCRIPTION (provided by applicant): Polyomavirus nephropathy (PVN) is a form of nephritis caused by reactivation of the human polyomavirus, BKV, in renal transplant patients. BKV is ubiquitous in most human populations and establishes a lifelong, subclinical, persistent infection of the kidney. In transplant patients and other immunocompromised individuals, viral replication leads to tissue damage and renal dysfunction. The incidence of PVN has risen dramatically in recent years concomitant with the development of more effective immunosuppressive drug regimens aimed towards preventing rejection of the transplant. Presently, there are no effective anti-viral treatments for BKV, and therefore the clinician is faced with the dilemma of reducing the dose of immunosuppressive drugs so as to allow the patient's immune system to battle the virus, which then raises the risk of rejection. The biology of BKV is not well understood, particularly in human kidney epithelial cells. Such an understanding will be critical in the rational design of therapeutic approaches. Using an in vitro cell culture system for the propagation of primary human proximal tubule epithelial (HPTE) cells, which allows them to maintain their differentiated function, the life cycle of BKV can be studied in detail. Preliminary results indicate that BKV replicates efficiently in these cells, thereby reproducing the situation in the immunosuppressed patient. The long-term aims of this project are to utilize this in vitro system to characterize the details of the viral life cycle and to define conditions that will prevent viral replication similar to those the virus would encounter in a healthy host. A detailed investigation of viral gene expression will be performed. In addition, a thorough analysis of the interactions between the virus and the host cell, focusing on the role of chemokines and cytokines in modulating the infection, will be undertaken. The findings from these in vitro studies will be correlated with an examination of biopsies obtained from patients undergoing renal transplantation at the University of Michigan Hospital to confirm that the in vitro observations mimic the events that occur in the patient. The results of the proposed studies will greatly enhance our knowledge of the mechanism by which BKV is reactivated in the absence of a functioning immune system and therefore point the way to better treatment modalities.

描述（由申请人提供）：多瘤病毒肾病（PVN）是肾移植患者中人类多瘤病毒BKV的重新激活引起的肾炎形式。 BKV在大多数人群中无处不在，并建立了肾脏的终生，亚临床，持续感染。 在移植患者和其他免疫功能低下的个体中，病毒复制会导致组织损伤和肾功能障碍。 近年来，PVN的发病率急剧上升，这与旨在防止拒绝移植的更有效的免疫抑制药物方案的发展。 目前，BKV没有有效的抗病毒治疗方法，因此临床医生面临着减少免疫抑制药物剂量的困境，以便使患者的免疫系统与病毒作斗争，从而增加了抑制风险。 BKV的生物学尚不清楚，尤其是在人类肾上皮细胞中。 这种理解对于治疗方法的合理设计至关重要。 使用体外细胞培养系统来传播原代人近端小管上皮（HPTE）细胞，从而使它们能够保持其不同的功能，可以详细研究BKV的生命周期。 初步结果表明，BKV在这些细胞中有效地复制，从而再现了免疫抑制患者的情况。 该项目的长期目的是利用该体外系统来表征病毒生命周期的细节，并定义将防止病毒复制的疾病，类似于病毒在健康宿主中会遇到的病毒。 将对病毒基因表达进行详细研究。 此外，将对病毒与宿主细胞之间的相互作用进行详尽的分析，重点是趋化因子和细胞因子在调节感染中的作用。 这些体外研究的发现将与密歇根大学医院接受肾脏移植的患者获得的活检的检查有关，以确认模仿患者发生的事件的体外观察。 拟议研究的结果将大大增强我们对在没有功能性免疫系统的情况下重新激活BKV的机制的知识，因此为更好的治疗方式提供了道路。