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Discovering fundamental metabolic control processes of the blood brain barrier

发现血脑屏障的基本代谢控制过程

基本信息

批准号：
8606786
负责人：
ROLAND J BAINTON
金额：
$ 23.4万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606786
关键词：
Acquired Immunodeficiency Syndrome Alzheimer&apos s Disease Anatomic structures Animals Arbitration B-Lymphocytes Blood - brain barrier anatomy Brain CCL21 gene Cell Adhesion Molecules Cells Chemicals Chemoprotection Communication Complex Data Data Set Diffusion Drosophila genus Drug Delivery Systems Drug Transport Elements Enzymes Exclusion Financial compensation Foundations Future Gene Expression Profile Genes Genetic Genomics Goals Homeostasis Homologous Gene Hypoxia Individual Investigation Knock-out Link Logic Maintenance Malignant Neoplasms Mammals Messenger RNA Metabolic Metabolic Control Metabolic Pathway Metabolic stress Methods Modification Molecular Mus Natural Immunity Nervous System Physiology Neuraxis Neuroglia Neurons Nutrient Orthologous Gene Pathway interactions Pharmaceutical Preparations Physiological Physiology Process Property Regulation Relative (related person)Signal Transduction Signaling Molecule Stress Stroke Subcellular Anatomy Surface System Testing Tight Junctions Tissues Toxin Translating Vascular Endothelium Vertebrates Xenobiotic Metabolism cell type chemical function comparative genomics cost design fly gene function genetic manipulation improved insight interstitial mutant nervous system disorder novel operation perineural public health relevance response small molecule tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Central nervous system (CNS) physiology requires special chemical, metabolic and cellular privileges for normal function, and blood brain barrier (BBB) structures are the anatomic and physiologic constructs that arbitrate communication between the brain and body. A functionally integrated set of chemical protection properties established by the genes expressed in BBB cell layers combine to control small molecule access to the CNS. A better description of the fundamental metabolic control processes at the BBB is a key roadblock in understanding CNS physiology under hypoxic, metabolic and chemical stress conditions. Furthermore the vast majority of drugs do not pass into the brain because of the same highly integrated chemical protection mechanisms of the BBB. In order to better understand metabolic control of the brain space, the physical means and organizational logic behind the many independent chemical exclusion operations performed by the BBB must be determined. The Drosophila BBB, a glially derived barrier, possesses similar physiologic properties, highly homologous genetic components, and similar cellular anatomy to the vertebrate BBB. Furthermore Drosophila genetic tools allow for systematic and rapid interrogation of multiple BBB cell layers in whole animals and under normal physiological conditions thus localizing specific chemical isolation and communication mechanisms with great precision. To decipher essential BBB components and specific control elements at multiple levels the BBB transcriptome is an invaluable tool. In preliminary studies a precise transcriptional profile of the fly BBB was produced and bioinformatically compared to similar vertebrate BBB data sets that include the vascular endothelium (VE) and associated astrocytic glia (AG). The initial analysis shows remarkable functional similarities between Drosophila and vertebrate BBBs as hundreds of highly homologous genes are greatly enriched in both data sets including many metabolic transporters. These data suggest that a set of highly evolutionary conserved physiologies is present at the cellular layers of the BBB. This proposal uses the power of the Drosophila BBB system and comparative genomics to discover cell autonomous chemical protection mechanisms, intercellular compensations, and systemic signals that regulate BBB function. It weaves together genetic, genomic, and physiologic methods to deepen our understanding of the complex integration of sophisticated cellular anatomy and highly polarized chemical protection physiology. With these insights it will be possible to decipher the rules of chemical isolation and assign best use target pathways for getting drugs into the brain. Ultimately, these insights will deliver novel testable hypothesis to vertebrate systems for future studies in genetic or chemical modulating of BBB function.

描述（由申请人提供）：中枢神经系统（CNS）生理学需要特殊的化学、代谢和细胞特权才能实现正常功能，血脑屏障（BBB）结构是仲裁大脑和身体之间通信的解剖和生理结构。由BBB细胞层中表达的基因建立的一组功能整合的化学保护特性联合收割机控制小分子进入CNS。更好地描述BBB的基本代谢控制过程是理解缺氧、代谢和化学应激条件下CNS生理学的关键障碍。此外，绝大多数药物不会进入大脑，因为BBB具有相同的高度整合的化学保护机制。为了更好地理解脑空间的代谢控制，必须确定BBB执行的许多独立化学排斥操作背后的物理手段和组织逻辑。果蝇血脑屏障是一种胶质源性屏障，具有与脊椎动物血脑屏障相似的生理特性、高度同源的遗传成分和相似的细胞解剖结构。此外，果蝇遗传工具允许在整个动物和正常生理条件下系统和快速地询问多个BBB细胞层，从而非常精确地定位特定的化学隔离和通信机制。为了在多个水平上破译必需的BBB组件和特定控制元件，BBB转录组是一个非常宝贵的工具。在初步研究中，产生了果蝇BBB的精确转录谱，并与包括血管内皮（VE）和相关星形胶质细胞（AG）的类似脊椎动物BBB数据集进行了生物信息学比较。初步分析显示果蝇和脊椎动物BBB之间具有显着的功能相似性，因为数百个高度同源的基因在两个数据集中都非常丰富，包括许多代谢转运蛋白。这些数据表明，一组高度进化保守的生理存在于血脑屏障的细胞层。该提案利用果蝇血脑屏障系统和比较基因组学的力量来发现细胞自主化学保护机制，细胞间补偿和调节血脑屏障功能的系统信号。它编织在一起遗传，基因组和生理学方法，以加深我们对复杂的细胞解剖学和高度极化的化学保护生理学的复杂整合的理解。有了这些见解，就有可能破译化学隔离的规则，并分配最佳使用的靶向途径，使药物进入大脑。最终，这些见解将提供新的可验证的假设，脊椎动物系统的遗传或化学调节血脑屏障功能的未来研究。