Functional annotation of the oxidized lipid hydrolase PLA2G7 in neurodegeneration

氧化脂质水解酶 PLA2G7 在神经退行性变中的功能注释

基本信息

批准号：
9259700
负责人：
Daniel Hermanson
金额：
$ 1.74万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2017-07-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9259700
关键词：
ABHD12 gene Address Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Apolipoprotein E Arachidonic Acids Ataxia Atherosclerosis Biochemical Biological Assay Biological Models Blood Brain CD36 gene Cardiovascular Diseases Cataract Cells Chemicals Chronic Clinical Treatment Consequentialism DNA Microarray Chip Data Development Disease model Docosahexaenoic Acids Enzyme Inhibition Enzymes Gene Proteins Genes Genetic Glial Fibrillary Acidic Protein Hereditary Disease Human Human Genetics Hydrolase Hydrolysis Immune In Vitro Individual Inflammation Isotopes Laboratories Linoleic Acids Lipid Peroxidation Lipid Peroxides Lipids Lipoproteins Longitudinal Studies Maps Mass Spectrum Analysis Mediating Metabolic Methods Modeling Mus Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Odds Ratio Organism Oxides Palmitates Pathway interactions Patients Pharmacology Phase II Clinical Trials Phase III Clinical Trials Phospholipids Physiological Play Polyneuropathy Polyunsaturated Fatty Acids Positioning Attribute Proteins Proteolysis Proteomics Protocols documentation Risk Factors Role Serine Hydrolase Stearates Structure Techniques Therapeutic Therapeutic Effect Time Tissues Transgenic Mice activity-based protein profiling acute coronary syndrome age related apolipoprotein E-4 base brain tissue cell injury chemical genetics chemoproteomics clinical development experimental study functional outcomes hearing impairment high risk human disease in vivo inhibitor/antagonist innovation insight lipid metabolism liquid chromatography mass spectrometry mouse model neuroinflammation neuron loss oxidation oxidative damage oxidized lipid pre-clinical public health relevance therapy development tool

项目摘要

DESCRIPTION (provided by applicant): The PLA2G7 gene encodes a 50 kDa secreted serine hydrolase. Much of the focus on PLA2G7 has centered on its' potential as a marker for cardiovascular disease; however, PLA2G7 is expressed throughout the mammalian organism, including the brain. Inhibition of PLA2G7 has demonstrated therapeutic benefits in human patients with Alzheimer's disease, yet the in vivo function of the enzyme is poorly characterized. Our laboratory has developed a suite of tools to study the role of PLA2G7 in mouse brain including PLA2G7-/- mice, selective, centrally active inhibitors of PLA2G7, and target engagement assays to confirm inhibitor action in vivo. Using these chemical and genetic tools in combination with mass spectrometry-based lipidomic and proteomic studies we propose to determine the metabolic function of PLA2G7 in the central nervous system using longitudinal studies and define its role in two mouse models of neurodegeneration. In specific aim 1 we will map age-dependent lipid changes in the brains of PLA2G7-disrupted mice using PLA2G7-/- mice and the selective PLA2G7 inhibitor JMN21. These studies will utilize untargeted and targeted liquid chromatography- mass spectrometry to identify and quantify PLA2G7-dependent changes in brain metabolites. In specific aim 2 we will identify PLA2G7-dependent lipid changes in two animal models of neuroinflammation and neurodegeneration: ABHD12-/- mice, a mouse model of the rare human genetic disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract), and B6.Cg-Tg(GFAP- APOE_i4)1Hol Apoetm1Unc/J (apoE4) mice, a mouse model for Alzheimer's disease. Approximately 15% of humans harbor the apoE ε4 allele, but it is present in at least 40% of patients with late-onset AD; additionally individuals with one ε4 allele are three to four times more likely to develop AD and individuals with homozygous ε4 alleles have twelve times higher risk, an odds ratio much greater than that of other late-onset AD risk factors. PLA2G7 is directly associated with apoE, ideally positioning it to modulate metabolic changes, particularly as pertains to lipid oxidation, in apoE4 transgenic mice. In specific aim 3 we will determine the functional contribution of PLA2G7-regulated lipid pathways to neuroinflammation and neurodegeneration in ABHD12-/- and apoE4 mice. We anticipate that these studies will provide descriptive metabolic analyses and consequential functional outcomes of PLA2G7 inhibition or deletion with significant relevance to human conditions, including PHARC and Alzheimer's disease, the most prevalent neurodegenerative disorder. Identification of the metabolic function of PLA2G7 and correlating the metabolic changes imparted by PLA2G7 deletion or inhibition with therapeutic effects in ABHD12-/- and apoE4 mice will provide a greater understanding of PLA2G7 function and identify the basis for its therapeutic effects in human disease.

描述（由适用提供）：PLA2G7基因编码50 kDa分泌的丝氨酸水解酶。对PLA2G7的大部分关注都集中在其作为心血管疾病标志的潜力上。但是，PLA2G7在包括大脑在内的整个哺乳动物生物体中表达。 PLA2G7的抑制作用表明了阿尔茨海默氏病的人类患者的热益处，但酶的体内功能的特征很差。我们的实验室已经开发了一套工具来研究PLA2G7在小鼠脑中的作用，包括PLA2G7 - / - 小鼠，选择性，中心活跃的PLA2G7和目标参与刺客，以确认体内抑制剂作用。使用这些化学和遗传工具与基于质谱的脂肪组和蛋白质组学研究结合使用，我们建议使用纵向研究确定PLA2G7在中枢神经系统中的代谢功能，并定义其在两种神经变性小鼠模型中的作用。在特定的目标1中，我们将使用PLA2G7 - / - 小鼠和选择性PLA2G7抑制剂JMN21绘制PLA2G7-脱离小鼠大脑中的年龄依赖性脂质变化。这些研究将利用未靶向和靶向的液相色谱 - 质谱法来识别和量化脑代谢产物中PLA2G7依赖性变化。在特定目标2中，我们将在两个神经炎症和神经变性的动物模型中鉴定依赖PLA2G7的脂质变化：ABHD12 - / - 小鼠，这是一种罕见人遗传疾病的小鼠模型PHARC（多神经病，听力损失，共济失调，开发率，视网膜病毒copmentosa和capoe），以及B6.CG-TG-ape_cg-TG。 apoetm1unc/j（ApoE4）小鼠，是阿尔茨海默氏病小鼠模型。大约15％的人类藏有ApoEε4等位基因，但至少40％的患有晚期发病的患者中存在。此外，具有一ε4等位基因的个体发展AD的可能性高三到四倍，并且具有纯合ε4等位基因的个体的风险高十二倍，优势比大得多，远大于其他晚发的AD AD风险因素。 PLA2G7与APOE直接相关，理想地将其定位为调节代谢变化，尤其是与脂质氧化有关的APOE4转基因小鼠。在特定目标3中，我们将确定PLA2G7调节的脂质途径对ABHD12 - / - 和APOE4小鼠中神经炎症和神经变性的功能贡献。我们预计，这些研究将提供描述性的代谢分析和PLA2G7抑制或缺失的结果功能结果，并与人类疾病（包括PHARC和Alzheimer氏病），最普遍的神经退行性疾病（包括PHARC和阿尔茨海默氏病）有显着相关性。识别PLA2G7的代谢功能并将PLA2G7缺失或抑制作用与ABHD12-/ - 和APOE4小鼠的治疗作用相关的代谢变化将提供对PLA2G7功能的更多了解，并确定其在人类疾病中的治疗作用的基础。