Ras and Chemokine Stimulated Neutrophil Polarization

Ras 和趋化因子刺激中性粒细胞极化

• 批准号: 6596957
• 负责人: CINDY M KNALL
• 金额: $ 10万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6596957
• 关键词: biological signal transduction; cellular polarity; chemokine; clinical research; cytokine receptors; guanine nucleotide binding protein; human subject; interleukin 8; neutrophil; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Polymorphonuclear leukocytes, neutrophils, are the most abundant leukocytes in peripheral blood. They play a major role in innate immunity and may contribute to the development of the adaptive immune response. The early and selective recruitment of neutrophils into inflamed tissues is thought to be a major factor in the tissue damage/destruction seen in a number of disease states. The chemokines Interleukin-8 (IL8) and Growth-Regulated Oncogene alpha (GROalpha) control much of the normal function of neutrophils. These chemokines are also implicated in the diseases associated with neutrophil dysfunction. Research is beginning to investigate the specific signal transduction pathways activated by these chemokines to regulate neutrophil functions. Our long-range goal is to define the signal transduction mechanisms used by chemokines to activate neutrophils in order to develop effective therapeutic strategies to regulate this activation. Polarization is the first step in the process of neutrophil migration into sites of inflammation. However, the signal transduction pathways that regulate chemokine stimulated neutrophil polarization remain undefined. The objective of this proposal is to determine the mechanisms that induce chemokine stimulated neutrophil polarization. The central hypothesis of this proposal is that IL8, in contrast to GROalpha regulates neutrophil polarization independent of phosphatidylinositol-3 (PI3) kinase because IL8 stimulates a more robust activation of several different signal transduction molecules. This hypothesis is based on strong preliminary data that suggest that efficient activation of Ras by IL8, in contrast to GROalpha allows for PI3 kinase independent regulation of neutrophil polarization, because IL8 binds to both CXCR1 and CXCR2. The rationale for the proposed research is that once the mechanisms controlling neutrophil polarization are defined, effective therapies can be developed to control this process. The central hypothesis will be tested and the objective accomplished through two specific aims: 1) identify the signal transduction molecule that allows IL8 to by-pass PI3 kinase in the regulation of neutrophil polarization; 2) determine the extent to which the chemokine receptors CXCR1 and CXCR2 contribute to PI3 kinase independent neutrophil polarization. The proposed work is innovative because it utilizes a technique, recently developed by the applicant, to transfect primary human neutrophils. Our expectation is that this approach establish how IL8 and GROalpha regulate neutrophil polarization using two different mechanisms. This outcome is significant because it will suggest new targets for prevention and treatment strategies to control neutrophil recruitment in a variety of inflammatory diseases such as obliterative bronchiolitis, the most significant long-term complication in lung transplant patients. The proposed study fulfills the scope of the NIAID small research grants program as a small, self-contained research project requiring minimal funding for a limited time.

描述（由申请人提供）：多形核白细胞，中性粒细胞是外周血中最丰富的白细胞。它们在先天免疫中起着重要作用，并可能有助于自适应免疫反应的发展。将中性粒细胞募集到发炎组织中的早期和选择性募集被认为是许多疾病状态下组织损伤/破坏的主要因素。趋化因子白介素8（IL8）和生长调节的癌基因α（groalpha）控制中性粒细胞的许多正常功能。这些趋化因子也与与中性粒细胞功能障碍相关的疾病有关。研究开始研究这些趋化因子激活的特定信号转导途径以调节中性粒细胞功能。我们的远程目标是定义趋化因子用于激活中性粒细胞的信号转导机制，以制定有效的治疗策略以调节这种激活。极化是中性粒细胞迁移到炎症部位的第一步。然而，调节趋化因子刺激中性粒细胞极化的信号转导途径仍然不确定。该建议的目的是确定诱导趋化因子刺激中性粒细胞极化的机制。该提议的中心假设是，与斑纹相比，IL8与磷脂酰肌醇3（PI3）激酶相比调节中性粒细胞极化，因为IL8刺激了几种不同信号转导分子的更强大的激活。该假设是基于强大的初步数据，该数据表明，与斑点相比，IL8有效激活RAS，可以对PI3激酶独立地调节中性粒细胞极化，因为IL8与CXCR1和CXCR2结合。拟议研究的理由是，一旦定义了中性粒细胞极化的机制，就可以开发出有效的疗法来控制这一过程。中央假设将进行测试，并通过两个特定目的完成目标：1）确定允许IL8在中性粒细胞极化的调节中逐通PI3激酶的信号转导分子； 2）确定趋化因子受体CXCR1和CXCR2在多大程度上有助于PI3激酶独立的中性粒细胞极化。 拟议的工作具有创新性，因为它利用申请人最近开发的一种技术来转染原代人性粒细胞。 我们的期望是，这种方法确定了IL8和Groalpha如何使用两种不同的机制来调节中性粒细胞极化。这种结果很重要，因为它将提出预防和治疗策略的新靶标，以控制各种炎症性疾病中的中性粒细胞募集，例如闭塞性细支气管炎，这是肺移植患者中最重要的长期并发症。拟议的研究履行了NIAID小型研究补助计划的范围，这是一个小型，独立的研究项目，需要在有限时间内最少的资金。