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）：血脑屏障是一层内皮细胞，排列在中枢神经系统的血管中，并由星形胶质细胞等其他中枢神经系统细胞支持以实现正常功能。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的影响。由于其保护功能，血脑屏障阻碍治疗化合物进入中枢神经系统，从而阻碍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渗透性，以允许治疗药物进入大脑，因为这将对多种神经系统疾病的治疗产生重大影响。这些疾病包括阿尔茨海默病、帕金森病、癫痫、艾滋病毒/艾滋病的神经系统表现、狼疮的神经系统后遗症、亨廷顿舞蹈症、脑癌等等。有前景的疗法可用于治疗多种此类疾病，但由于血脑屏障造成的巨大障碍，此类疗法的功效尚未实现。我们最近有了新的发现，细胞外腺苷（一种由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，我们试图阐明血脑屏障水平上腺苷信号传导的分子和细胞机制，重点是使用 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传导调节内皮屏障功能。我们将在三个具体目标中对此进行测试： 1．具体目标 1：确定腺苷受体信号传导调节 WT 和阿尔茨海默病转基因小鼠血脑屏障通透性的程度。 2. 具体目标2：阐明AR信号调节脑内皮细胞通透性的分子机制。 3.具体目标3：确定腺苷受体的激活是否允许抗β淀粉样蛋白抗体进入CNS以结合并改变阿尔茨海默病转基因小鼠模型中的神经炎斑块。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，并揭示将其用作药物输送系统可治疗从阿尔茨海默病到脑肿瘤等多种神经系统疾病。公共健康相关性：血脑屏障可以保护大脑免受血液中潜在有害成分的影响，但是这种保护功能使得治疗化合物很难进入大脑来治疗阿尔茨海默氏症等神经系统疾病和根除艾滋病毒等传染病。我们有强有力的初步数据证明细胞外腺苷；人体自然产生的一种分子可以增加血脑屏障的通透性，促进治疗药物等物质进入大脑。该提案中提出的研究将帮助我们了解腺苷控制血脑屏障的机制，并确定 FDA 批准的腺苷能药物是否可以用作向大脑输送治疗药物的方法。