Equilibrative Nucleoside Transporters during AKI

AKI 期间的平衡核苷转运蛋白

• 批准号: 8857231
• 负责人: Holger K. Eltzschig
• 金额: $ 51.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857231
• 关键词: ADORA2B gene; Acute; Acute Lung Injury; Acute Renal Failure with Renal Papillary Necrosis; Address; Adenosine; Affect; Attenuated; Binding; Biological Assay; Biopsy; Cells; Chronic; Chronic Disease; Collaborations; Dipyridamole; Disease; Disease Progression; Drug Targeting; Epithelium; Event; Genetic; Goals; Human; Hypoxia; Hypoxia Inducible Factor; Individual; Inflammation; Injury; Injury to Kidney; Instruction; Ischemia; Kidney; Kidney Diseases; Laboratories; Lung; Mediating; Metabolic; Modeling; Morbidity - disease rate; Mus; Nucleoside Transporter; Oxygen; Pathway interactions; Patients; Phenotype; Play; Public Health; Purinergic P1 Receptors; Renal function; Reperfusion Therapy; Repression; Role; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Staging; Therapeutic; Tissues; Transcriptional Regulation; Tubular formation; Vascular Endothelium; Ventilator; Work; adenosine transporter; base; body system; extracellular; gene therapy; genetic approach; inhibitor/antagonist; insight; lung injury; mortality; mouse model; novel; renal epithelium; renal ischemia; response; transcription factor; uptake

Acute kidney injury (AKI) is among the leading cause of morbidity and mortality of hospitalized patients, and novel treatment options are urgently needed. The main goal of this proposal is to identify the functional contributions of adenosine transporters to renal protection from AKI. Moreover, we will utilize our findings in AKI to better understand the hypoxic adenosine response in acute or chronic states of lung injury and sickle cell disease (SCD). As such, our findings will address functional differences of extracellular adenosine during disease progression from acute injury into chronic disease states. Adenosine signaling plays an important role in tissue adaptation during hypoxia. Adenosine's effects are terminated via uptake from the extracellular towards the intracellular compartment through equilibrative nucleoside transporters (ENTs). Studies from our laboratory show that inhibition of ENTs enhances adenosine signaling during hypoxia and promotes protection from AKI. Studies in mice with genetic deletion of Enti or Ent2 identified a selective phenotype in Entl'^' mice, including higher adenosine levels, preserved kidney function, and attenuated inflammation. Subsequent studies of ENT inhibitor treatment in mice with deletion of individual adenosine receptors suggested the AD0RA2B adenosine receptor mediates kidney protection from AKI. Therefore, we hypothesize that inhibition or deletion of ENTI promotes kidney protection from ischemia by increasing extracellular adenosine and signaling events through the AD0RA2B. Four specific aims are proposed: Aim 1: Define the cell-specific contributions of ENTs during AKI, Aim 2: Study the transcriptional control of ENTs during ischemic AKI, Aim 3: Study the cell-specific functions of adenosine receptors in ENT-dependent kidney protection during ischemic AKI, and Aim 4: Study the role of the hypoxic adenosine response in AKI- driven lung injury. Together, these studies will provide novel insight into how the hypoxic adenosine response varies among different organ systems, which will help guide the use of adenosine-based therapeutics for kidney, lung and SCD associated disorders.

急性肾损伤（阿基）是住院患者发病率和死亡率的主要原因之一， 迫切需要新的治疗选择。本提案的主要目标是确定 腺苷转运蛋白对肾保护免受阿基的贡献。此外，我们将利用我们的研究结果， 阿基，以更好地了解急性或慢性肺损伤和镰状状态下的缺氧腺苷反应 细胞疾病（SCD）。因此，我们的研究结果将解决细胞外腺苷的功能差异， 从急性损伤到慢性疾病状态的疾病进展。腺苷信号传导在 在缺氧时组织适应中的作用。腺苷的作用是通过从细胞外的 通过平衡型核苷转运蛋白（ENTs）向细胞内区室转运。我们的研究 实验表明，在缺氧期间，抑制ENTs增强腺苷信号传导， 保护阿基。在具有Entl或Ent2的遗传缺失的小鼠中的研究鉴定了在小鼠中的选择性表型。 在小鼠中，包括更高的腺苷水平、保留的肾功能和减弱的炎症。 在缺失单个腺苷受体的小鼠中进行ENT抑制剂治疗的后续研究 表明AD0RA2B腺苷受体介导肾保护免受阿基。所以我们 假设ENTI抑制或缺失通过增加肾脏缺血保护作用， 细胞外腺苷和通过AD0RA2B的信号传导事件。提出了四个具体目标： 目的1：确定ENT在阿基中的细胞特异性作用，目的2：研究ENT的转录调控 目的3：研究腺苷受体在缺血性阿基中的细胞特异性功能， 目的4：研究缺氧腺苷反应在缺血性阿基中的作用。 驱动性肺损伤总之，这些研究将提供新的见解如何缺氧腺苷 不同器官系统的反应不同，这将有助于指导使用基于腺苷的 用于肾、肺和SCD相关病症的治疗剂。