Equilibrative Nucleoside Transporters during AKI

急性肾损伤(AKI)是住院患者发病率和死亡率的主要原因之一， 迫切需要新的治疗方案。此建议的主要目标是确定功能 腺苷转运体在急性肾损伤肾脏保护中的作用。此外，我们将利用我们的发现在 Aki以更好地了解急性或慢性肺损伤和镰刀状状态下的缺氧腺苷反应 细胞病(SCD)。因此，我们的发现将解决细胞外腺苷在细胞外的功能差异。 疾病从急性损伤进展到慢性疾病状态。腺苷信号转导起着重要的作用 在组织低氧适应中的作用。腺苷的作用通过从细胞外摄取而终止 通过平衡的核苷转运体(Ents)进入细胞内。来自我们的研究 实验室研究表明，抑制Ents可增强低氧时的腺苷信号转导，促进 保护您免受AKI攻击。对具有entI或ent2基因缺失的小鼠的研究发现，在 Entl‘^’小鼠，包括更高的腺苷水平，保存的肾功能，以及减轻炎症。 单个腺苷受体缺失的ENT抑制剂治疗小鼠的后续研究 提示AD0RA2B腺苷受体介导AKI对肾脏的保护作用。因此，我们 假说抑制或缺失enti通过增加肾脏对缺血的保护 胞外腺苷和通过AD0RA2B的信号事件。提出了四个具体目标：目标 1：确定Ents在AKI过程中的细胞特异性贡献，目标2：研究Ents的转录调控 缺血AKI期间，目标3：研究ENT依赖中腺苷受体的细胞特异性功能 缺血AKI时的肾脏保护，以及目标4：研究缺氧性腺苷反应在AKI中的作用 导致肺损伤。总之，这些研究将为低氧性腺苷如何 不同器官系统的反应不同，这将有助于指导腺苷类药物的使用 治疗肾、肺和SCD相关疾病。 相关性(请参阅说明)： 肾脏和肺的急性损伤是常见的和毁灭性的。我们对基础知识知之甚少 这些疾病中的组织保护机制。本申请中提出的工作将寻求定义 治疗急性损伤的新药物靶点可为公众提供重大进展 健康。

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. RELEVANCE (See instructions): Acute injury to the kidney and the lung are common and devastating. We know little about the basic mechanisms of tissue protection in these disorders. The work proposed in this application will seek to define novel drug targets for the treatment of acute injuries that could provide significant advancements to public health.