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（由申请人提供）：PLA2G7 基因编码 50 kDa 的分泌型丝氨酸水解酶，人们对 PLA2G7 的关注主要集中在其作为心血管疾病标志物的潜力；然而，PLA2G7 在整个哺乳动物有机体（包括大脑）中表达。 PLA2G7 的抑制已证明对患有阿尔茨海默氏病的人类患者有治疗作用，但该酶的体内功能尚不清楚，我们的实验室已开发出一套酶。研究 PLA2G7 在小鼠大脑中的作用的工具，包括 PLA2G7-/- 小鼠、PLA2G7 的选择性、中枢活性抑制剂，以及使用这些化学和遗传工具与基于质谱的结合来确认抑制剂体内作用的靶点接合测定。脂质组学和蛋白质组学研究我们建议通过纵向研究确定 PLA2G7 在中枢神经系统中的代谢功能，并确定其在两种小鼠神经退行性变模型中的作用。使用 PLA2G7-/- 小鼠和选择性 PLA2G7 抑制剂 JMN21 检测 PLA2G7 破坏小鼠大脑中年龄依赖性脂质变化。这些研究将利用非靶向和靶向液相色谱-质谱法来识别和量化大脑代谢物中 PLA2G7 依赖性的变化。在具体目标 2 中，我们将在两种神经炎症和神经变性动物模型中确定 PLA2G7 依赖性脂质变化： ABHD12-/- 小鼠、罕见人类遗传性疾病 PHARC（多发性神经病、听力损失、共济失调、视网膜色素变性和白内障）的小鼠模型和 B6.Cg-Tg(GFAP- APOE_i4)1Hol Apoetm1Unc/J (apoE4) 小鼠大约 15% 的人类携带 apoE ε4 等位基因，但它是一种阿尔茨海默病小鼠模型。至少 40% 的晚发性 AD 患者存在这种现象；此外，具有 1 个 ε4 等位基因的个体患 AD 的可能性高出 3 到 4 倍，而具有纯合 ε4 等位基因的个体患 AD 的风险高出 12 倍，比值比远高于此。 PLA2G7 与 apoE 直接相关，理想情况下它可以调节 apoE4 转基因中的代谢变化，特别是与脂质氧化有关的变化。在具体目标 3 中，我们将确定 PLA2G7 调节的脂质途径对 ABHD12-/- 和 apoE4 小鼠的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代谢分析以及 PLA2G7 抑制或缺失的相应功能结果。与人类状况密切相关，包括 PHARC 和阿尔茨海默氏病，这是最常见的神经退行性疾病，鉴定 PLA2G7 的代谢功能并关联代谢。 PLA2G7 缺失或抑制所带来的变化对 ABHD12-/- 和 apoE4 小鼠具有治疗作用，这将有助于更好地了解 PLA2G7 功能，并确定其在人类疾病中的治疗作用的基础。