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2,3 cAMP in Traumatic Brain Injury

2,3 cAMP 在创伤性脑损伤中的作用

基本信息

批准号：
9100931
负责人：
EDWIN Kerry JACKSON
金额：
$ 33.69万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9100931
关键词：
2&apos -adenylic acid Adenosine Age Alkaline Phosphatase Astrocytes Biochemical Biochemistry Brain Brain Injuries Cells Cyclic AMP Cyclic Nucleotides Development Enzymes Evolution Goals Health Human Hypoxia Injury Isomerism Knockout Mice Left Mechanics Mediating Metabolic stress Metabolism Microglia Mitochondria Myelin Myelin Proteins Neurologic Neurons Neuroprotective Agents Neurosciences Neurotoxins Oligodendroglia Outcome P-Glycoproteins Pathway interactions Permeability Play Process Production Public Health Purines Reaction Research Personnel Rodent Second Messenger Systems System Testing Tissues Toxin Traumatic Brain Injury axonal degeneration body system cell type central nervous system injury design extracellular improved outcome in vivo mRNA Transcript Degradation mitochondrial permeability transition pore neurotoxic new therapeutic target novel novel strategies novel therapeutics phosphoric diester hydrolase research study response to injury second messenger tandem mass spectrometry

项目摘要

DESCRIPTION (provided by applicant): The term "cAMP" usually refers to the second messenger 3',5'-cyclic adenosine monophosphate. We serendipitously discovered that organ systems can produce (from mRNA degradation) and export to the extracellular compartment a positional isomer of 3',5'-cAMP, namely 2',3'-cAMP. We showed that organ systems convert extracellular 2',3'-cAMP to 2'-AMP + 3'-AMP and can metabolize 2'-AMP and 3'-AMP to adenosine. We refer to this pathway as the "2',3'-cAMP-adenosine pathway." We also showed that extracellular 2',3'-cAMP increases greatly post-traumatic brain injury (TBI) in brain in rodents and humans; and that when the pathway is impaired, TBI outcomes worsen in rodents. Intracellular 2',3'-cAMP opens mitochondrial permeability transition pores while extracellular adenosine is neuroprotective. Thus the "2',3'- cAMP-adenosine pathway" may be important in TBI because it eliminates an intracellular neurotoxin (export of 2',3'-cAMP) and generates an extracellular neuroprotectant (conversion of 2',3'-cAMP to adenosine). We also identified the enigmatic myelin protein 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) to be the major enzyme that metabolizes extracellular 2',3'-cAMP to 2'-AMP (a key step toward conversion into adenosine). KO mice lacking CNPase produce less extracellular adenosine post-TBI, are more susceptible to injury and develop axonal degeneration with age despite no gross myelin abnormalities. Hypothesis: the "2',3'-cAMP- adenosine pathway" is an endogenous cytoprotective mechanism after TBI. We will elucidate which CNS cell types produce 2',3'-cAMP, what kinds of injury trigger 2',3'-cAMP production, how 2',3'-cAMP is transported out of cells, how downstream AMPs are converted to adenosine, and if manipulating the 2',3'-cAMP-adenosine pathway alters secondary damage. Specific Aim 1: To determine which CNS cell types produce 2',3'-cAMP after injury. Because in vivo TBI increases extracellular 2',3'-cAMP, it is important to determine which CNS cells produce 2',3'-cAMP and whether the effect is injury-type dependent. Aim 1 will determine if metabolic stress, hypoxia or mechanical injury enhances 2',3'-cAMP production by astrocytes, microglia, neurons or oligodendrocytes. Specific Aim 2: To determine whether Multidrug Resistance Protein 4 (MRP4) mediates egress of 2',3'-cAMP. Because 2',3'-cAMP is an intracellular toxin, it is critical to elucidate how 2',3'-cAMP is extrude from CNS cells. Aim 2 will test the hypothesis that MRP4 exports 2',3'-cAMP. Specific Aim 3: To determine if Tissue Alkaline Phosphatase (TAP) participates in the extracellular metabolism of 2'-AMP and 3'- AMP (downstream metabolites of 2',3'-cAMP) to adenosine. Because extracellular adenosine is neuroprotective it is essential to understand how extracellular 2'-AMP and 3'-AMP are converted to extracellular adenosine. Specific Aim 4: To test the hypothesis that the 2',3'-cAMP-adenosine pathway is an endogenous protective mechanism post-TBI. Aim 4 will further test the hypothesis that the 2',3'-cAMP- adenosine pathway is cytoprotective by determining the effect of inhibiting or augmenting it on TBI outcomes.

说明（由申请人提供）：术语“cAMP”通常是指第二信使3 '，5'-环腺苷一磷酸。我们偶然发现，器官系统可以产生（从mRNA降解）并输出到细胞外室的3 '，5'-cAMP的位置异构体，即2 '，3'-cAMP。我们发现，器官系统将细胞外的2 '，3'-cAMP转化为2 '-AMP +3'-AMP，并且可以将2 '-AMP和3'-AMP代谢为腺苷。我们将该途径称为“2 '，3'-cAMP-腺苷途径。“我们还表明，细胞外2 '，3'-cAMP大大增加了啮齿动物和人类大脑的创伤后脑损伤（TBI）;当该途径受损时，啮齿动物的TBI结果会恶化。细胞内2 '，3'-cAMP打开线粒体通透性转换孔，而细胞外腺苷具有神经保护作用。因此，“2 '，3'-cAMP-腺苷途径”在TBI中可能是重要的，因为它消除细胞内神经毒素（2 '，3'-cAMP的输出）并产生细胞外神经保护剂（2 '，3'-cAMP转化为腺苷）。我们还确定了神秘的髓鞘蛋白2 '，3'-环核苷酸3 '-磷酸二酯酶（CNE 3）是将细胞外2'，3 '-cAMP代谢为2'-AMP（转化为腺苷的关键步骤）的主要酶。敲除小鼠缺乏CNclase产生更少的细胞外腺苷后TBI，更容易受到损伤，并发展轴突变性与年龄，尽管没有严重的髓鞘异常。假设：“2 '，3'-cAMP-腺苷途径”是TBI后的内源性细胞保护机制。我们将阐明哪些CNS细胞类型产生2 '，3'-cAMP，什么类型的损伤触发2 '，3'-cAMP的产生，2 '，3'-cAMP如何被运输出细胞，下游AMP如何转化为腺苷，以及操纵2 '，3'-cAMP-腺苷途径是否会改变继发性损伤。具体目的1：确定哪些CNS细胞类型在损伤后产生2 '，3'-cAMP。因为体内TBI增加细胞外2 '，3'-cAMP，所以重要的是确定哪些CNS细胞产生2 '，3'-cAMP以及该作用是否是损伤类型依赖性的。目的1将确定代谢应激、缺氧或机械损伤是否增强星形胶质细胞、小胶质细胞、神经元或少突胶质细胞的2 '，3'-cAMP产生。具体目的2：确定多药耐药蛋白4（MRP 4）是否介导2 '，3'-cAMP的排出。由于2 '，3'-cAMP是一种细胞内毒素，因此阐明2 '，3'-cAMP是如何从CNS细胞中挤出的至关重要。目的2将检验MRP 4输出2 '，3'-cAMP的假设。具体目标3：确定组织碱性磷酸酶（TAP）是否参与细胞外2 '-AMP和3'-AMP（2 '，3'-cAMP的下游代谢产物）代谢为腺苷。由于细胞外腺苷具有神经保护作用，因此了解细胞外2 '-AMP和3'-AMP如何转化为细胞外腺苷至关重要。具体目的4：检验2 '，3'-cAMP-腺苷途径是TBI后内源性保护机制的假设。目的4将通过确定抑制或增强2 '，3'-cAMP-腺苷途径对TBI结果的影响来进一步检验2 '，3'-cAMP-腺苷途径具有细胞保护性的假设。