Brain endothelial cell function under adenosine receptor signaling directive

腺苷受体信号传导下的脑内皮细胞功能

• 批准号: 9095570
• 负责人: Margaret S. Bynoe
• 金额: $ 10万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095570
• 关键词: ADORA2A gene; Acquired Immunodeficiency Syndrome; Actins; Adenosine; Adherens Junction; Affect; Agonist; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Astrocytes; Binding; Biochemical; Biological Models; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Body Fluids; Brain; Brain Neoplasms; Cell Line; Cell Shape; Cell Size; Cell physiology; Cells; Central Nervous System Diseases; Chemicals; Communicable Diseases; Cytoskeleton; Data; Disease; Disease model; Drug Delivery Systems; Drug Kinetics; Endothelial Cells; Epilepsy; FDA approved; Goals; HIV; Health; Homeostasis; Human; Huntington Disease; In Vitro; Light; Lupus; Malignant neoplasm of brain; Mediating; Methods; Molecular; Mouse Cell Line; Multi-Drug Resistance; Multidrug Resistance Gene; Mus; Neuraxis; Neurologic; Neurologic Manifestations; Outcome Study; P-Glycoprotein; Parkinson Disease; Permeability; Pharmaceutical Preparations; Proteins; Purine Nucleosides; Purinergic P1 Receptors; Receptor Signaling; Regulation; Research Personnel; Role; Scientific Advances and Accomplishments; Senile Plaques; Signal Transduction; Structure; Supporting Cell; Technology; Testing; Therapeutic; Tight Junctions; Time; Transgenic Mice; Treatment Efficacy; adenosine receptor activation; capillary; cell type; extracellular; intravital microscopy; mouse model; nervous system disorder; novel; prevent; rho GTP-Binding Proteins; two-photon

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.

描述（由申请人提供）：血脑屏障是一层内皮细胞，排列在中枢神经系统的血管上，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稳态，保护大脑免受血液循环中潜在有害物质的侵害。由于其保护功能，血脑屏障阻碍了治疗性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。我们迫切需要能够安全有效地调节血脑屏障的渗透性，使治疗药物能够进入大脑，因为这将对各种神经系统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/艾滋病的神经系统症状、狼疮的神经系统后遗症、亨廷顿氏病、脑癌等等。有希望的治疗方法可用于治疗广泛的这些疾病，但由于血脑屏障构成的巨大障碍，这些治疗方法的疗效尚未实现。我们最近有了新的发现，胞外腺苷，一种由身体产生的嘌呤核苷，是脑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重耐药基因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的分子和细胞机制，重点是通过fda批准的A2A腺苷受体激动剂Lexiscan打开血脑屏障。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对此进行测试。具体目的1：确定腺苷受体信号在WT和阿尔茨海默氏症转基因小鼠中调节血脑屏障通透性的程度。2. 特异性目的2：阐明AR信号调节脑内皮细胞通透性的分子机制。3. 特异性目的3：确定腺苷受体的激活是否允许抗-淀粉样蛋白抗体进入中枢神经系统，结合并改变阿尔茨海默病转基因小鼠模型中的神经斑块。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的潜力