Prostacyclin (PG12) Regulation of RSV-induced Illness

前列环素 (PG12) 对 RSV 引起的疾病的调节

• 批准号: 7056097
• 负责人: Ray Stokes Peebles
• 金额: $ 33.18万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056097
• 关键词: T lymphocyte; antigen presenting cell; biological signal transduction; cellular immunity; disease /disorder model; enzyme activity; gene expression; genetically modified animals; immunologic memory; immunoregulation; laboratory mouse; microorganism immunology; prostacyclins; prostaglandin endoperoxide synthase; prostaglandin receptor; respiratory infections; respiratory syncytial virus

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease in infants and a significant cause of mortality in transplant patients and the elderly. Adequate therapy and vaccines are not currently available. Our preliminary data in a murine model of RSV infection strongly suggests that prostacyclin (PGI2) represents an effective novel therapy for severe RSV-induced illness. Mice that constitutively overexpress PGI 2 synthase are significantly protected against RSV-induced weight loss and mortality, and have reduced viral titers compared to nontransgenic littermates. The objective of this application is to define the mechanism by which PGI2 synthase overexpression confers protection against RSV. The specific aims are to: 1) Define the immunomodulatory effect of signaling through the PGI2 receptor (known as "IP") on RSV-induced illness. We hypothesize that PGI 2 signaling through IP will protect against illness caused by RSV. To test this hypothesis, we will use mice in which IP has been knocked-out (IPKO), use mice in which the overexpression ofPGI z synthase can be induced, and use PGI 2 analogs in our in vivo system of RSV infection; 2) Determine the effect ofPGI 2 on antigen presenting cell (APC) differentiation and function. We hypothesize that PGI 2 upregulates APC differentiation and function, enhancing the T cell response to RSV infection. To test this hypothesis, we will define the effect ofPGI 2 synthase overexpression on the quantity and activation of APCs in the lung after RSV infection, and also determine the effect ofa PGI z analog on in vitro APC differentiation; and 3) Determine the contribution ofT lymphocytes to theproteetion conferredbyPGI z synthase overexpressioninRSV-inducedillness. We hypothesize thatthepfincipal mechanism by which PGI 2 synthase overexpressing mice are protected against RSV-induced illness is an effect on lymphocytes. To test this hypothesis, we will define the functional T cell subset and memory response to RSV infection in PGI 2 synthase overexpressing and wild type mice. The proposed studies will define the mechanism by which PGI 2 modulates the immune response to RSV infection and protects against RSV-induced disease.

描述（由申请人提供）：呼吸道合胞病毒（RSV）是婴儿严重下呼吸道疾病的最重要原因，也是移植患者和老年人死亡的重要原因。目前尚无足够的治疗方法和疫苗。我们在 RSV 感染小鼠模型中的初步数据强烈表明，前列环素 (PGI2) 是治疗 RSV 引起的严重疾病的有效新疗法。组成型过表达 PGI 2 合酶的小鼠可显着免受 RSV 诱导的体重减轻和死亡的影响，并且与非转基因同窝小鼠相比，病毒滴度降低。本申请的目的是确定 PGI2 合酶过度表达可提供针对 RSV 的保护的机制。具体目标是： 1) 确定通过 PGI2 受体（称为“IP”）的信号传导对 RSV 引起的疾病的免疫调节作用。我们假设通过 IP 发出的 PGI 2 信号将预防 RSV 引起的疾病。为了检验这一假设，我们将使用IP已被敲除的小鼠（IPKO），使用可诱导PGI z合酶过度表达的小鼠，并在我们的RSV感染体内系统中使用PGI 2类似物； 2)确定PGI 2对抗原呈递细胞(APC)分化和功能的影响。我们假设 PGI 2 上调 APC 分化和功能，增强 T 细胞对 RSV 感染的反应。为了检验这一假设，我们将确定RSV感染后PGI 2合酶过度表达对肺中APC数量和活化的影响，并确定PGI z类似物对体外APC分化的影响； 3)确定T淋巴细胞对RSV诱导的疾病中PGI z合酶过度表达所赋予的保护的贡献。我们假设 PGI 2 合酶过表达小鼠免受 RSV 诱导疾病的主要机制是对淋巴细胞的影响。为了检验这一假设，我们将定义 PGI 2 合酶过度表达和野生型小鼠的功能性 T 细胞亚群和对 RSV 感染的记忆反应。拟议的研究将确定 PGI 2 调节 RSV 感染免疫反应并预防 RSV 诱发疾病的机制。