Trangenic Mouse Breeding Core

该计划项目赠款(PPG)的主要目标是定义低氧引起的海拔高度的作用 急慢性疾病状态下的细胞外腺苷和伴随的信号事件。条件 低氧与细胞外腺苷的强劲增加有关。这里，我们建立在假设的基础上 特别是AD0RA2B腺苷受体在调节细胞反应中起着核心作用 在低氧条件下。在炎症、缺氧或缺血的情况下，缺氧引起 胞外腺苷的升高足以激活AD0RA2B。这是因为低氧 通过低氧诱导因子的活性协调AD0RA2B的转录诱导 HIF。此外，最近的研究揭示了增强AD0RA2B信号的另一种机制 在缺氧期间。这涉及到细胞外腺苷终止的缺氧依赖性减弱。 通过细胞外腺苷摄取减少而进入细胞内的信号传递。这种分子 该途径是由依赖于HIF的腺苷转运体，特别是ent1和ent2的抑制所控制的。 这个PPG的三个项目都集中在低氧诱导的细胞外腺苷信号的增加， 包括HIF对AD0RA2B信号转导和ENTS的影响。因此，它将是成功的核心 PPG拥有最先进的鼠标模型来测试每个单独项目中的假设。 这种转基因小鼠育种核心将提供具有细胞特异性缺失的最先进的小鼠模型 缺氧性腺苷反应的关键基因，以便各个项目可以解决他们的 假设。转基因小鼠育种核心将提供以下服务：1.代和 具有细胞特异性关键元件缺失的转基因小鼠系的初步特征 低氧性腺苷反应，以及2.将特定小鼠品系的大量繁育种群交付给 适当的项目负责人。总之，这些努力将增进我们对腺苷和 调节疾病，并推动我们朝着治疗各种疾病的新疗法的方向发展 肺和肾。 相关性(请参阅说明)： 这一核心将为个别项目提供MICE，以深入了解信号分子的作用 腺苷在调节致命的肺、肾和镰状细胞疾病中的作用。这一信息将使 为这些流行和致命的疾病开发新的治疗方法。

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.