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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：
9122112
负责人：
Daniel Hermanson
金额：
$ 5.43万
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 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9122112
关键词：
ABHD12 gene Address Alleles Alzheimer&apos s Disease Animal Model Apolipoprotein E Arachidonic Acids Ataxia Atherosclerosis Biochemical Biological Assay Biological Models Blood Brain CD36 gene Cardiovascular Diseases Cataract Cells Chemicals Chronic Clinical Clinical Treatment DNA Microarray Chip Data Development Disease 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 Laboratories Linoleic Acids Lipid Peroxidation Lipids Lipoproteins Longitudinal Studies Maps Mass Spectrum Analysis Mediating Metabolic Methods Modeling Mus Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Odds Ratio Organism Palmitates Pathway interactions Patients 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 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 oxidized lipid pre-clinical public health relevance research study 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.