Brain endothelial cell function under adenosine receptor signaling directive

描述(申请人提供)：血脑屏障是一层内皮细胞，排列在中枢神经系统的血管内，并由其他中枢神经系统细胞(如星形胶质细胞)支持以发挥正常功能。血脑屏障的功能是维持中枢神经系统的动态平衡，保护大脑免受血液中循环的潜在有害物质的影响。由于血脑屏障的保护作用，它阻碍了治疗化合物进入中枢神经系统，从而阻止了许多神经系统疾病的治疗。非常需要能够安全有效地调节血脑屏障的通透性，以允许治疗药物进入大脑，因为这将对各种神经疾病的治疗产生重大影响。这些疾病包括阿尔茨海默氏症、帕金森氏症、癫痫、艾滋病毒-艾滋病的神经表现、狼疮的神经后遗症、亨廷顿病、脑癌等等。有希望的治疗方法可以治疗这些疾病的广泛范围，然而，由于血脑屏障构成的巨大障碍，这些治疗的有效性尚未实现。我们最近有了一个新的发现，细胞外腺苷，一种由体内产生的嘌呤核苷，是脑血管内皮细胞通透性的关键调节剂。我们也有初步证据表明，胞外腺苷可能调节多药耐药基因P-糖蛋白的表达和功能。在这项研究中，我们试图阐明腺苷信号在血脑屏障水平上的分子和细胞机制，重点是用FDA批准的A2A腺苷受体激动剂Lexiscan开放血脑屏障。我们的中心假设是脑内皮细胞中的腺苷受体信号调节内皮屏障功能。我们将在三个具体目标中测试这一点。具体目标1：明确腺苷受体信号在多大程度上调节WT和阿尔茨海默病转基因小鼠的血脑屏障通透性。2.具体目的2：阐明AR信号调节脑血管内皮细胞通透性的分子机制。3.具体目标3：在阿尔茨海默病转基因小鼠模型中，确定腺苷受体的激活是否允许抗β淀粉样抗体进入中枢神经系统，以结合和改变神经性斑块。这些研究的结果将为腺苷在血脑屏障调节中的作用提供新的信息，并阐明将其作为一种 药物输送系统，用于治疗从阿尔茨海默氏症到脑瘤的各种神经系统疾病。

DESCRIPTION (provided by applicant): The blood brain barrier is a layer of endothelial cells that line the blood vessels in the central nervous system and is supported by other CNS cells such as astrocytes for proper function. The function of the blood brain barrier is to maintain the homeostasis of the CNS and protect the brain from potentially harmful substances circulating in the blood. Owing to its protective function, the blood brain barrier hinders the entry of therapeutic compounds into the central nervous system thereby prohibiting treatment of many neurological diseases. There is a tremendous need to be able to safely and effectively modulate the permeability of the blood brain barrier to allow entry of therapeutic drugs into the brain, as this would have a major impact on treatment for a broad variety of neurological diseases. These include Alzheimer's, Parkinson's, epilepsy, neurological manifestations of HIV-AIDS, neurological sequelae of Lupus, Huntington's disease, brain cancer and many more. Promising therapies are available to treat a wide range of these disorders, however the efficacy of such therapies are not being realized due to the tremendous hurdle posed by the blood brain barrier. We have recently made the novel discovery that extracellular adenosine, a purine nucleoside produced by the body, is a critical modulator of brain endothelial cell permeability. We also have preliminary evidence suggesting that extracellular adenosine may regulate the expression and function of multi drug resistant gene, P-glycoprotein. In this study, we seek to elucidate the molecular and cellular mechanism of adenosine signaling at the level of the blood brain barrier with focus on opening blood brain barrier with the FDA-approved A2A adenosine receptor agonist, Lexiscan. Our central hypothesis is that adenosine receptor signaling in brain endothelial cells regulates endothelial barrier function. We will test this in three specific aims.1. Specific Aim 1: Define the extent to which adenosine receptor signaling modulates blood brain barrier permeability in WT and Alzheimer's transgenic mice. 2. Specific Aim 2: Elucidate the molecular mechanisms by which AR signaling modulates brain endothelial cell permeability. 3. Specific Aim 3: Determine whether activation of adenosine receptors allows entry of anti-beta amyloid antibodies into the CNS to bind to and alter neuritic plaques in an Alzheimer's disease transgenic mouse model. The outcome of these studies will provide new information on adenosine's role in blood brain barrier regulation and shed light on the potential to use this as a drug delivery system to treat a variety of neurological diseases ranging from Alzheimer's to brain tumors.