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

基本信息

批准号：
8438816
负责人：
Margaret S. Bynoe
金额：
$ 30.44万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8438816
关键词：
Acquired Immunodeficiency Syndrome Actins Adenosine Adenosine A2A Receptor Adherens Junction Affect Agonist Alzheimer&apos 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 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

项目摘要

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. PUBLIC HEALTH RELEVANCE: The blood brain barrier serves to protect the brain from potentially harmful components in the blood, however this protective function makes it very difficult to get therapeutic compounds into the brain to treat neurological diseases such Alzheimer's and to eradicate infectious diseases such as HIV. We have strong preliminary data that demonstrate that extracellular adenosine; a molecule naturally produced by the body can increase the permeability of the blood brain barrier to promote the entry of substances such as therapeutic drugs into the brain. The studies set out in this proposal will help us to understand the mechanism of adenosine's control of the blood brain barrier and to determine if FDA approved adenosinergic drugs can be used as a method of delivering therapeutic drugs to the brain.

描述（由申请人提供）：血脑屏障是在中枢神经系统中排列血管的内皮细胞层，并得到其他中枢神经系统细胞（如星形胶质细胞）的支持。血脑屏障的功能是维持中枢神经系统的稳态，并保护大脑免受血液中循环的潜在有害物质。由于其保护功能，血脑屏障阻碍了治疗化合物进入中枢神经系统，从而禁止治疗许多神经系统疾病。非常需要能够安全有效地调节血脑屏障的渗透性，以使治疗药物进入大脑，因为这将对多种神经系统疾病的治疗产生重大影响。其中包括阿尔茨海默氏症，帕金森氏症，癫痫，艾滋病毒的神经系统表现，狼疮的神经系统后遗症，亨廷顿氏病，脑癌等。有希望的疗法可用于治疗各种疾病，但是由于血脑屏障带来的巨大障碍，这种疗法的功效并未实现。我们最近提出了一个新的发现，即人体产生的嘌呤核苷是脑内皮细胞通透性的关键调节剂。我们还有初步证据表明，细胞外腺苷可能调节多耐药基因P-糖蛋白的表达和功能。在这项研究中，我们试图阐明血脑屏障水平上腺苷信号传导的分子和细胞机制，重点是用FDA批准的A2A A2A腺苷受体激动剂Lexiscan打开血液脑屏障。我们的中心假设是脑内皮细胞中的腺苷受体信号传导调节内皮屏障功能。我们将以三个特定目标进行测试1。具体目标1：定义腺苷受体信号传导在WT和阿尔茨海默氏症转基因小鼠中调节血脑屏障的渗透性的程度。 2。特定目标2：阐明AR信号传导调节脑内皮细胞通透性的分子机制。 3。特定目标3：确定腺苷受体的激活是否允许将抗β淀粉样蛋白抗体进入中枢神经系统中，以与阿尔茨海默氏病转基因小鼠模型中的神经斑结合和改变神经斑。这些研究的结果将提供有关腺苷在血脑屏障调节中的作用的新信息，并阐明了将其用作的潜力药物输送系统治疗从阿尔茨海默氏症到脑肿瘤等各种神经疾病。公共卫生相关性：血脑屏障可以保护大脑免受血液中潜在有害成分的侵害，但是这种保护功能使得将治疗化合物进入大脑非常困难，以治疗如阿尔茨海默氏病这样的神经系统疾病并消除诸如HIV等感染性疾病。我们有强大的初步数据，证明了细胞外腺苷。人体自然产生的分子可以增加血脑屏障的渗透性，以促进物质的进入，例如治疗药物进入大脑。该提案中规定的研究将有助于我们了解腺苷对血脑屏障的控制机制，并确定是否可以将FDA批准的腺苷能药物用作将治疗药物输送到大脑的方法。