Trangenic Mouse Breeding Core

这项计划项目补助金（PPG）的主要目标是确定缺氧引起的 细胞外腺苷和伴随的信号事件在急性与慢性疾病状态。条件 缺氧与细胞外腺苷的大量增加有关。在这里，我们建立在假设 特别是AD0RA2B腺苷受体在调节细胞反应中起着重要作用， 在缺氧的条件下。在炎症、缺氧或缺血条件下，缺氧引起的 细胞外腺苷的增加足以激活AD0RA2B。这是因为缺氧 通过低氧诱导因子的活性协调AD0RA2B的转录诱导 HIF。此外，最近的研究已经揭示了增强AD0RA2B信号传导的另外的机制 在缺氧的时候。这涉及细胞外腺苷终止的缺氧依赖性衰减 通过细胞外腺苷进入细胞内区室的摄取减少来进行信号传导。这种分子 这种途径受腺苷转运蛋白（特别是ENT1和ENT2）的HIF依赖性抑制控制。 该PPG的所有三个项目都集中在缺氧引起的细胞外腺苷信号传导的增加， 包括HIF对AD0RA2B信号传导和ENT的影响。因此，它将是成功的核心 PPG的最新技术水平的小鼠模型可用于测试每个项目中的假设。 该转基因小鼠育种核心将提供具有细胞特异性缺失的最新小鼠模型 缺氧腺苷反应的关键基因，以便各个项目可以解决他们的问题。 假设转基因小鼠育种中心将提供以下服务：1。生成和 对具有细胞特异性缺失的转基因小鼠品系的初步表征 缺氧腺苷反应，和2.将特定小鼠品系的大量繁殖群交付给 合适的项目负责人。总之，这些努力将提高我们对腺苷的认识， 调节疾病，并推动我们发展新的疗法来治疗各种疾病， 肺和肾 相关性（参见说明）： 该核心将为各个项目提供小鼠，以深入了解信号分子的作用 腺苷在致命的肺，肾和镰状细胞病的调节。这些信息将有利于 为这些流行且致命的疾病开发新的疗法。

The main goal of this Program Project Grant (PPG) is to define the role of hypoxia-elicited elevations of extracellular adenosine and concomitant signaling events in acute versus chronic disease states. Conditions of hypoxia are associated with robust increases in extracellular adenosine. Here, we build on the hypothesis that particularly the AD0RA2B adenosine receptor plays a central role in modulating cellular responses during conditions of hypoxia. During conditions of inflammation, hypoxia, or ischemia, the hypoxia-elicited rise in extracellular adenosine is sufficient to activate the AD0RA2B. This is due to the fact that hypoxia coordinates the transcriptional induction of the AD0RA2B through the activity of hypoxia-inducible factor HIF. Moreover, recent studies have revealed an additional mechanism to enhance AD0RA2B signaling during hypoxia. This involves hypoxia-dependent attenuation of the termination of extracellular adenosine signaling via decreased uptake of extracellular adenosine into the intracellular compartment. This molecular pathway is governed by HIF-dependent repression of adenosine transporters, particularly ENTI and ENT2. All three projects of this PPG focus on hypoxia-elicited increases of extracellular adenosine signaling, including the effects of HIF on AD0RA2B signaling and on ENTs. Therefore, it will be central to the success of the PPG to have state of the art mouse models available to test hypotheses in each individual project. This Transgenic Mouse Breeding Core will provide state of the art mouse models with cell-specific deletions of key genes of the hypoxic adenosine response so that the individual projects can address their hypotheses. The Transgenic Mouse Breeding Core will provide the following services: 1. Generation and initial characterization of transgenic mouse lines with cell-specific deletions of key elements within the hypoxic adenosine response, and 2. Delivery of large breeding stocks of specific mouse lines to the appropriate Project Leaders. Together, these efforts will enhance our knowledge of adenosine and the regulation of disease and move us towards the development of novel therapies to treat various diseases of the lungs and the kidneys. RELEVANCE (See instructions): This Core will provide mice to individual Projects to gain insight into the role of the signaling molecule adenosine in the regulation of deadly lung, kidney and sickle cell disease. This information will benefit the development of novel therapies for these diseases, which are prevalent and deadly.