Purinergic receptors in inflammation

炎症中的嘌呤能受体

• 批准号: 8287705
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287705
• 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

PURINERGIC RECEPTORS IN INFLAMMATION - 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. Narrative 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.

炎症中的嘌呤能受体-趋化性使多形核中性粒细胞（PMN） 以迅速到达感染和发炎的部位。然而，过多的PMN流入会损害宿主组织。更好 了解控制中性粒细胞趋化性的机制可能有助于改善炎症性疾病的治疗。 疾病基于我们最近的研究结果，ATP和腺苷参与了PMN的趋化，我们提出， 来研究如何调节嘌呤能信号传导过程来防止组织损伤。嘌呤能 信号传导有三个基本组成部分：i）细胞外ATP和腺苷的来源; ii）嘌呤能 对ATP和腺苷应答的受体，和iii）通过以下途径调节细胞应答的外核苷酸酶： 将ATP水解成腺苷。这一建议基于以下工作假设： 趋化剂从PMN释放ATP。ATP激活附近的P2 Y2受体，放大梯度 感应A3腺苷受体被募集到前沿，在那里腺苷由CD 39/E- NTPD酶1和碱性磷酸酶（ALP）。腺苷和通过A3受体的正反馈驱动细胞 通过A2 a受体的负反馈促进细胞后部的膜收缩。 干扰这些嘌呤能信号传导过程可抑制趋化性，从而改善PMN诱导的趋化性。 脓毒症和创伤患者的组织损伤和器官衰竭。 将处理以下具体目标： 1. PMN释放ATP的机制：本节将重点讨论PMN释放ATP的机制。 细胞ATP对趋化刺激的反应。具体而言，我们将重点关注参与 hTTYH 3最大阴离子通道、连接蛋白半通道和脱粒。 2.腺苷形成的机制：设计实验来检查主要的外核苷酸酶 负责将释放的ATP转化为腺苷。主要重点将放在 NTPDase 1和ALP的作用。 3.嘌呤能信号复合物：我们将探索趋化受体与ATP的共定位 释放位点，嘌呤能受体和外核苷酸酶，并研究嘌呤能信号簇， 由这些分子组成的分子提供了“局部激发和全局抑制”，如理论上提出的。 趋化性模型 4.嘌呤能信号在体内的作用：我们将研究P2 Y2，A3，A2 a，NTPD酶1和ALP的作用。 在小鼠模型中，并测试靶向这些分子以防止宿主组织损伤的可行性。 拟议的研究有望提高我们对控制趋化性机制的理解。 这可能会导致新的治疗方法，以改善过度流入引起的宿主组织损伤 例如，在创伤和感染性休克患者中，叙事 趋化性是中性粒细胞在健康和疾病中的一个关键功能反应，目前对它的认识还很有限。在这 我们计划确定细胞ATP和嘌呤能受体的释放如何控制趋化性， 这种控制机制是否可以被靶向地预防炎症和宿主组织 创伤患者的损伤。