Purinergic receptors in inflammation

炎症中的嘌呤能受体

• 批准号: 8081813
• 负责人: WOLFGANG G JUNGER
• 金额: $ 35.09万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081813
• 关键词: ATP Receptors; Acute Lung Injury; Address; Adenosine; Adenosine A3 Receptor; Adenosine Triphosphate; Alkaline Phosphatase; Amino Acids; Anions; Area; Back; Cells; Chemical Structure; Chemicals; Chemotactic Factors; Chemotaxis; Complex; Connexins; Disease; Environment; F-Actin; Feedback; Health; Host Defense; Inflammation; Inflammatory; Knowledge; Lead; Mammalian Cell; Mediating; Membrane; Modeling; Multiple Organ Failure; Nucleosides; Nucleotides; Nutritional; Oligonucleotides; Organ; Organ failure; P2Y2 receptor; Patients; Peptides; Play; Process; Property; Purinergic P1 Receptors; Purinoceptor; Recruitment Activity; Rest; Role; Sepsis; Septic Shock; Signal Transduction; Signaling Molecule; Site; Source; Stimulus; System; Testing; Tetrahymena pyriformis; Tissues; Trauma; Work; autocrine; base; cell motility; computerized data processing; design; ecto-nucleotidase; ectoADPase; extracellular; improved; in vivo; migration; mouse model; neutrophil; novel therapeutic intervention; prevent; receptor; research study; response

DESCRIPTION (provided by applicant): Chemotaxis allows polymorphonuclear neutrophils (PMN) to rapidly reach infected and inflamed sites. However excessive influx of PMN damages host tissues. Better knowledge of the mechanisms that control PMN chemotaxis may lead to improved treatments of inflammatory diseases. Based on our recent findings that ATP and adenosine are involved in PMN chemotaxis, we propose to study here how to regulate this purinergic signaling process in order to prevent tissue damage. Purinergic signaling has three essential components: i) sources of the extracellular ATP and adenosine; ii) purinergic receptors that response to ATP and adenosine and, iii) ecto-nucleotidases that modulate cellular responses by hydrolyzing ATP to adenosine. This proposal is based on the following working hypothesis: Chemotactic agents release ATP from PMN. ATP activates nearby P2Y2 receptors, amplifying gradient sensing. A3 adenosine receptors are recruited to the leading edge where adenosine is generated by CD39/E- NTPDase1 and alkaline phosphatase (ALP). Adenosine and positive feedback through A3 receptors drives cell migration, while negative feedback through A2a receptors facilitates membrane retraction at the back of cells. Interfering with these purinergic signaling processes inhibits chemotaxis, which ameliorates PMN-induced tissue damage and organ failure in sepsis and trauma patients. The following specific aims will be addressed: 1. Mechanism of ATP release from PMN: This section will focus on the mechanisms by which PMN release cellular ATP in response to chemotactic stimulation. Specifically, we will focus on the involvement of hTTYH3 tweety maxi-anion channels, connexin hemi-channels, and degranulation. 2. Mechanism of adenosine formation: Experiments are designed to examine the major ecto-nucleotidases that are responsible for the conversion of released ATP to adenosine. Major emphasis will be placed on the contributions of NTPDase1 and ALP. 3. Purinergic signaling complexes: We will explore the co-localization of chemotactic receptors with ATP release sites, purinergic receptors, and ecto-nucleotidases and investigate if purinergic signaling clusters, comprised of these molecules provide "local excitation and global inhibition" as proposed in theoretical chemotaxis models. 4. Role of purinergic signaling in vivo: We will study the roles of P2Y2, A3, A2a, and NTPDase1 and ALP in mouse models and test the feasibility of targeting these molecules to prevent host tissue damage. The proposed studies are expected to improve our understanding of the mechanisms that control chemotaxis. This could lead to novel therapeutic approaches to ameliorate host tissue damage caused by excessive influx of activated PMN, for example, in trauma and septic shock patients. PUBLIC HEALTH RELEVANCE: Chemotaxis, a key functional response of neutrophils in health and disease is still poorly understood. In this project we propose to determine how release of cellular ATP and purinergic receptors control chemotaxis and whether this control mechanism can be pharmacologically targeted to prevent inflammation and host tissue damage in trauma patients.

描述（由申请人提供）：趋化性允许多形核中性粒细胞（PMN）迅速到达感染和发炎的位点。但是，PMN损坏的过度流入宿主组织。更好地了解控制PMN趋化性的机制可能会导致改善炎症性疾病的治疗方法。根据我们最近的发现，即ATP和腺苷参与PMN趋化性，我们建议在这里研究如何调节这种嘌呤能信号传导过程，以防止组织损伤。嘌呤能信号传导具有三个基本组成部分：i）细胞外ATP和腺苷的来源； ii）对ATP和腺苷反应的嘌呤能受体以及iii）核苷酸酶，可通过水解ATP向腺苷调节细胞反应。该建议基于以下工作假设：趋化剂从PMN释放ATP。 ATP激活附近的P2Y2受体，扩大梯度感应。 A3腺苷受体被募集到由CD39/E-NTPDase1和碱性磷酸酶（ALP）产生的腺苷的前缘。通过A3受体的腺苷和阳性反馈驱动细胞迁移，而通过A2A受体的负反馈促进了细胞背面的膜回缩。干扰这些嘌呤能信号传导过程会抑制趋化性，从而缓解败血症和创伤患者中PMN诱导的组织损伤和器官衰竭。将解决以下具体目标：1。从PMN释放ATP的机理：本节将重点介绍PMN释放细胞ATP响应趋化性刺激的机制。具体而言，我们将重点关注HTTYH3 Tweety Maxi-Anion通道，连接蛋白半通道和脱粒。 2。腺苷形成的机理：实验旨在检查负责释放ATP转化为腺苷的主要核苷酸酶。将重点放在NTPDASE1和ALP的贡献上。 3。嘌呤能信号传导复合物：我们将探索与ATP释放位点，嘌呤能受体和核核苷酸酶的趋化受体的共定位，并研究是否由这些分子组成的嘌呤能信号传导簇，这些分子是否提供了“局部激发”和“全球抑制”，如理论化的化学毒素模型。 4。嘌呤能信号在体内的作用：我们将研究P2Y2，A3，A2A和NTPDASE1和ALP在小鼠模型中的作用，并测试针对这些分子以防止宿主组织损伤的可行性。预计拟议的研究将提高我们对控制趋化性机制的理解。这可能会导致新型的治疗方法，以减轻因激活PMN涌入（例如，在创伤和败血性休克患者中）引起的宿主组织损伤。公共卫生相关性：趋化性，中性粒细胞在健康和疾病中的关键功能反应仍然知之甚少。在该项目中，我们建议确定细胞ATP和嘌呤能受体的释放如何控制趋化性，以及该控制机制是否可以在药理上靶向以防止创伤患者的炎症和宿主组织损伤。