Role of PARP-1 in Salmonella Pathogenesis

PARP-1 在沙门氏菌发病机制中的作用

• 批准号: 6875004
• 负责人: MITCHELL C JUNG
• 金额: $ 31.04万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875004
• 关键词: SDS polyacrylamide gel electrophoresis; Salmonella infections; Salmonella typhimurium; autoradiography; bioterrorism /chemical warfare; cell death; cysteine endopeptidases; disease /disorder prevention /control; enzyme activity; enzyme induction /repression; enzyme linked immunosorbent assay; gel mobility shift assay; gene expression; immune response; laboratory mouse; lipopolysaccharides; macrophage; membrane potentials; microarray technology; pathologic process; pentosyltransferase; septic shock; site directed mutagenesis; tissue /cell culture; transcription factor; western blottings

DESCRIPTION (provided by applicant): Salmonella, a potential bioterrorism agent (NIAID Category B Priority Pathogens), can cause life threatening systemic infections. Our objective is to understand the role of poly(ADP-ribose) polymerase-1(PARP-1) in Salmonella pathogenesis. Recently, PARP-1-deficient (PARP-1-/-) mice and tissue have been shown to be resistant to inflammatory stimuli. Our preliminary studies indicate that PARP-1-/- mice are resistant to Salmonella typhimurium induced septic shock, suggesting that PARP-1 plays an essential role in Salmonella pathogenesis. Additionally, PARP-1 is known to mediate inflammatory-type necrotic cell death and regulate various transcription factors required for the inflammation associated gene expression. These events may be crucial for the outcome of Salmonella infection. Innate immune responses of macrophages are the first-line of defense against infection and therefore a critical parameter for determining the outcome of diseases. However, the role of PARP-1 on innate immune responses of S. typhimurium infected macrophages is currently unknown. Our hypotheses are (a) PARP-1 activity is induced during Salmonella infection and in turn mediates caspase-1-dependent macrophage cell death, and (b) PARP-1 regulates S. typhimurium LPS-induced specific transcription factors and associated inflammatory gene expression in macrophages. Our Aims are to (1) determine the role of PARP-1 in S. typhimurium infected macrophages and on S. typhimurium-induced caspase-1-dependent macrophage cell death, and (2) identify specific transcription factors and proinflammatory genes regulated by PARP-1 in S. typhimurium LPS-activated macrophages. R21 Mechanism: Our project is at an early stage of development, and our preliminary data are limited. The R21 mechanism will allow us to gather critical information regarding the role of PARP-1 on innate immune responses of S. typhimurium infected macrophages. These preliminary studies will be critical for a future R01 to determine the precise role of PARP-1 on Salmonella pathogenesis and to develop methods for the prevention and treatment of infection.

描述（由申请方提供）：沙门氏菌是一种潜在的生物恐怖剂（NIAID B类优先病原体），可导致危及生命的全身感染。我们的目的是了解聚（ADP-核糖）聚合酶-1（PARP-1）在沙门氏菌致病中的作用。 最近，PARP-1缺陷（PARP-1-/-）小鼠和组织已被证明对炎症刺激具有抗性。我们的初步研究表明，PARP-1-/-小鼠对鼠伤寒沙门氏菌诱导的脓毒性休克具有抗性，表明PARP-1在沙门氏菌的发病机制中起着重要作用。此外，已知PARP-1介导炎症型坏死性细胞死亡并调节炎症相关基因表达所需的各种转录因子。这些事件可能对沙门氏菌感染的结果至关重要。巨噬细胞的天然免疫应答是抵抗感染的第一道防线，因此是确定疾病结果的关键参数。然而，PARP-1在S.鼠伤寒感染的巨噬细胞目前是未知的。 我们的假设是：（a）PARP-1活性在沙门氏菌感染过程中被诱导，进而介导半胱天冬酶-1依赖性巨噬细胞死亡，（B）PARP-1调节沙门氏菌。鼠伤寒杆菌LPS诱导巨噬细胞中特异性转录因子和相关炎症基因表达。我们的目的是（1）确定PARP-1在S.鼠伤寒沙门氏菌感染的巨噬细胞和S.鼠伤寒沙门氏菌诱导的caspase-1依赖的巨噬细胞死亡，和（2）鉴定特定的转录因子和PARP-1调节的促炎基因在S.鼠伤寒杆菌LPS激活的巨噬细胞。 R21机制：我们的项目处于早期开发阶段，我们的初步数据有限。R21机制将使我们能够收集关于PARP-1在S.鼠伤寒杆菌感染的巨噬细胞。这些初步研究对于未来的R 01至关重要，以确定PARP-1对沙门氏菌发病机制的确切作用，并开发预防和治疗感染的方法。