Regulation of IFN-beta induction by P2X7 purinergic receptor signaling

P2X7 嘌呤能受体信号传导对 IFN-β 诱导的调节

• 批准号: 7936194
• 负责人: Judith Anne Smith
• 金额: $ 13.99万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936194
• 关键词: Adenine Nucleotides; Agonist; Antiviral Agents; Area; Autoimmune Diseases; Autoimmune Process; Basic Science; Binding; Biology; Blood Platelets; CD14 Antigen; Calcium; Calcium Signaling; Cations; Cells; Cessation of life; Clinical; Collaborations; Complex; Continuing Education; Cytolysis; Cytoplasmic Tail; Data; Dendritic cell activation; Development Plans; Developmental Process; Disease; Double-Stranded RNA; Employee Strikes; Endotoxins; Environment; Equipment; Faculty; Family; Funding; G-Protein-Coupled Receptors; Genes; Genetic Transcription; Goals; Immune; Immune response; Infection; Inflammation; Inflammatory; Interferon-beta; Interferons; Lead; Ligands; Ligation; Lipopolysaccharides; MAP Kinase Activation Pathway; MAP Kinase Signaling Pathways; MAPK14 gene; MAPK8 gene; Mediating; Medical; Membrane; Mentors; Messenger RNA; Mitogen-Activated Protein Kinases; Modification; Morphogenesis; Mus; Natural Immunity; Nitric Oxide; Nucleotides; Osteitis; Osteoporosis; P2X-receptor; Pathway interactions; Physicians; Play; Principal Investigator; Process; Production; Purine Nucleotides; Purines; Purinoceptor; Receptor Signaling; Regulation; Research; Research Project Grants; Role; Schools; Scientist; Sepsis; Signal Induction; Signal Transduction; Signal Transduction Pathway; Site; Stimulus; Study Section; TLR4 gene; Techniques; Testing; Time; Tissues; Training; Universities; Virus Diseases; Wisconsin; Work; adaptive immunity; analog; bactericide; bone; career; career development; chromatin immunoprecipitation; cytokine; extracellular; immunoregulation; improved; interest; macrophage; member; novel; nucleotide analog; nucleotide receptor; pediatric department; programs; promoter; purine; receptor; release of sequestered calcium ion into cytoplasm; response; small molecule; transcription factor

DESCRIPTION (provided by applicant): Goals: My long-term research goal is to gain a greater understanding of the regulation of type I IFN production by macrophages, cells that are key players in inflammation. As a physician-scientist, it is my hope that these studies will eventually contribute to the improved treatment of inflammatory and autoimmune conditions. My immediate career goal is to develop a viable independent research program. Research project: During inflammation, the occurrence of tissue damage leads to sufficient release of extracellular purine nucleotides to stimulate immune cells via purinergic receptors such as P2X7. Stimulation of P2X7 by ATP is well known to increase the production of inflammatory cytokines (e.g. IL-1¿) by macrophages stimulated with endotoxin (LPS). We have found that co-stimulation of macrophages with LPS and the ATP analogue BzATP greatly augments the induction of IFN- ¿ by LPS. Type I IFNs play important roles in diverse aspects of innate and adaptive immunity. As both IFN- ¿ and purinergic receptor signaling have been implicated in bacterial sepsis and bone morphogenesis, it is critical to understand the mechanism of how P2X7 modulates the induction of IFN- ¿. To begin dissecting the mechanism of how P2X7 exerts its effect, a multi-pronged approach is proposed: We will examine the effect of P2X7 ligation on IFN- ¿ induction by different infectious stimuli (e.g. LPS, dsRNA etc.) to determine whether P2X7 enhancement is LPS specific. P2X7 ligation is known to initiate multiple signal transduction pathways: the contribution of calcium and MAP-kinase signaling pathways to the effect of BzATP on IFN- ¿ induction will be analyzed. Finally, we will examine the recruitment of transcription factors to the IFN- ¿ gene promoter by chromatin immunoprecipitation to test our underlying hypothesis that P2X7 ligation leads to increased transcription factor occupancy of the ifnb1 promoter. Modification of transcription factor recruitment by P2X7 mediated signaling has ramifications for the enhancement of immune responses and bone biology. Career development plan: The two key components are close collaboration with Paul Bertics and more formal oversight by a mentoring committee. Paul Bertics has abundant expertise in my area of interest and an excellent track record in training junior faculty. In addition to Dr. Bertics, my committee is composed of three other very supportive and successful physician scientists. Research environment: Through the department of Pediatrics, I have been accorded lab space, protected time and initial start-up funds. The breadth of expertise present at the University of Wisconsin, through the Medical and Graduate schools, is tremendous. Any equipment or technical assistance I should require will be available. There are ample forums for intellectual exchange as well as continuing education in the clinical and basic sciences. RELEVANCE: Macrophages participate in many inflammatory processes including responses to infections and autoimmune diseases by secreting cytokines. My research proposes to study how substances that are released by tissue damage called "purines" regulate the production of the inflammatory cytokine IFN- ¿ by macrophages. Greater understanding of inflammatory processes may ultimately lead to the better treatment of disease.

描述（由适用提供）：目标：我的长期研究目标是对巨噬细胞对I型IFN产生的调节，这是炎症中关键参与者的细胞。作为身体科学家，我希望这些研究最终将有助于改善炎症和自身免疫性状况的治疗。我的直接职业目标是制定一个可行的独立研究计划。研究项目：在炎症期间，组织损伤的发生导致足够的细胞外嘌呤核寡聚体释放以刺激免疫细胞受体，例如P2X7。众所周知，ATP刺激P2X7可通过用内毒素（LPS）刺激的巨噬细胞增加炎症细胞因子（例如IL-1？）的产生。我们发现，巨噬细胞与LPS的共同刺激和ATP模拟BZATP大大增强了LPS诱导IFN-¿的诱导。 I型IFNS在先天和适应性免疫史的潜水员方面起着重要作用。由于败血症和骨形态发生都隐含了IFN-和嘌呤能受体信号传导，因此了解P2X7如何调节IFN-€的诱导的机制至关重要。为了开始解剖P2X7如何执行其效果的机制，提出了一种多管齐下的方法：我们将研究P2X7连接对不同传染性刺激（例如LPS，DSRNA等）诱导IFN-的影响，以确定P2X7增强是否增强LPS是LPS的特异性。已知P2X7连接启动多个信号转移途径：将分析钙和MAP-激酶信号通路对BZATP对IFN-诱导作用的贡献。最后，我们将通过染色质免疫沉淀来检验转录因子向IFNWE基因启动子募集的募集，以检验我们的基本假设，即P2X7连接导致IFNB1启动子的转录因子占用增加。 P2X7介导的信号传导对转录因子募集的修饰具有后果，以增强免疫反应和骨骼生物学。职业发展计划：这两个关键组成部分是与Paul Bertics的密切合作，并由心理委员会进行了更正式的监督。保罗·伯蒂奇（Paul Bertics）在我感兴趣的领域拥有最丰富的专业知识，并且在培训初级教师方面拥有出色的往绩。除了Bertics博士外，我的委员会还由另外三位非常支持和成功的身体科学家组成。研究环境：通过儿科部，我已经按照实验室空间，受保护的时间和初始启动资金。威斯康星大学通过医学和研究生院所展现的专业知识广泛。我需要的任何设备或技术援助都将提供。有足够的论坛进行智力交流以及临床和基础科学的继续教育。 相关性：巨噬细胞通过分泌细胞因子来参与许多炎症过程，包括对感染和自身免疫性疾病的反应。我的研究提案要研究如何通过组织损伤释放的物质如何调节巨噬细胞的炎症细胞因子IFNTO的产生。对炎症过程的更多了解最终可能导致对疾病的更好治疗。