Solving EPHX2 and PUFA Interactions in Anorexia Nervosa

解决神经性厌食症中 EPHX2 和 PUFA 的相互作用

基本信息

批准号：
9030130
负责人：
Pei-an (Betty) Shih
金额：
$ 36.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2016-06-21 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030130
关键词：
Affect Anorexia Nervosa Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Base of the Brain Biochemistry Biological Assay Biological Markers Cessation of life Data Development Diet Dietary Factors Disease Disease Outcome Disease Progression Eating Emaciation Enzymes Epoxide hydrolase Epoxy Compounds Exposure to Fasting Food Food Aversion Functional disorder Future Genes Genetic Glycols Health Hydrolase Inflammation Inflammatory Intake Intervention Knowledge Lead Link Lipids Measures Meat Mental Health Messenger RNA Metabolism Molecular Monitor Morbidity - disease rate Nutraceutical Outcome Pathogenesis Pathway interactions Patients Pharmacologic Substance Phenotype Play Polyunsaturated Fatty Acids Predisposition Prevention Prognostic Marker Proteins Protocols documentation Psychiatry Psychopathology Public Health Recurrence Relapse Research Design Risk Risk Factors Role Signal Transduction Susceptibility Gene System Testing Variant Weight Work base design disorder risk food challenge gene product genetic variant improved in vivo innovation insight longitudinal design mRNA Expression metabolomics mortality non-genetic risk variant therapy development trait treatment response

项目摘要

DESCRIPTION (provided by applicant): Anorexia nervosa (AN) is characterized by severely restrictive eating and emaciation, with high rates of morbidity, chronicity and mortality. Current treatments have high rates of relapse and recurrence, thus developing new and improved therapies is a high priority in mental and public health. While AN is highly heritable, identifying risk genes and associated mechanisms on AN pathophysiology has yet to be successful due to the lack of adequate knowledge on how genes interact with non-genetic risk factors. This study aims to fill this major knowledge gap in order to develop better prevention and treatments. We will examine how soluble epoxide hydrolase (sEH), the gene product of an AN susceptibility gene, EPHX2, affects AN psychopathology and outcome using a meal-challenge study design to elucidate the mechanisms by which EPHX2 affects AN. sEH is a key enzyme that affects lipid signaling functions of bioactive metabolites (termed oxylipins). It modulates cellular inflammation by converting anti-inflammatory epoxides of polyunsaturated fatty acids (PUFAs) to pro-inflammatory oxylipins. In our recent study we identified dysregulated lipidomic profiles and elevated in vivo sEH activity (assessed by oxylipin ratios) in AN patients. The increase of the in vivo sEH marker persisted in weight-recovered AN, further supporting our hypothesis that EPHX2 regulates sEH activity that induces a pro-inflammatory oxylipin shift, therefore elevated sEH may contribute not only to AN susceptibility but also illness course and outcome. Testing this hypothesis is important because if found true, sEH activity may serve as a useful biomarker to predict disease outcome and guide treatment development. PUFAs are precursors of oxylipins, therefore PUFAs may affect regulatory efficiency of sEH on oxlipins. AN patients are known for their strong aversion to meat-based fatty foods (rich in ω-6 PUFA), and we have shown that dietary ω-6:ω-3 PUFA ratio is decreased in AN patients, suggesting that dysregulation of the EPHX2 lipidomic pathway in AN may be influenced by their PUFA intake. Thus, we will test the hypothesis that in AN patients, the metabolism of oxylipins is perturbed due to an increase in sEH activity, and the degree of perturbation is PUFA-dependent, resulting in increased food aversion, a higher burden of psychopathology, and poor outcome. In Aim 1 we will test if EPHX2 metabolomic pathways are altered in anorexia nervosa through a ω-6 rich breakfast challenge. In Aim 2 we will emphasize the fundamental biochemistry and molecular mechanism of EPHX2 gene by assaying ex vivo sEH activity to assess its association with AN risk. We will also characterize EPHX2 variants to examine the effects of the EPHX2 non-synonymous SNPs (nsSNPs) on ex vivo sEH activity. In Aim 3, we will utilize pre-meal and post-meal AN psychopathologic traits and 3-month outcome data to assess sEH's role in AN illness course and outcome through a longitudinal design. This study is significant because it will provide insights into AN pathogenesis by the use of an innovative meal challenge protocol that will reveal how genetic and dietary factor work in concert to exert effects on AN risk, phenotypes, and outcome. The results of this study will unravel mechanisms by which EPHX2 affects AN, improves our ability to predict disease risk, monitor disease progression and treatment response, and lead to new targets for future nutraceutical and pharmaceutical developments.

描述（由适用提供）：厌食症（AN）的特征是严重限制性饮食和消瘦，发病率，慢性和死亡率高。当前的治疗率很高，因此救济和复发率很高，因此在心理和公共卫生方面开发了新的和改进的疗法是重中之重。虽然是高度遗传的，但要识别由于缺乏有关基因如何与非遗传危险因素相互作用的足够知识，因此有关病理生理学的风险基因和相关机制尚未成功。这项研究旨在填补这一主要知识差距，以发展更好的预防和治疗。我们将使用进餐 - 挑战研究设计设计固体环氧化物水解酶（SEH）是如何影响心理病理学和结果的基因产物，以阐明EPHX2影响A的机制。 SEH是一种关键酶，影响生物活性代谢产物（称为Oxylipins）的脂质信号传导功能。它通过转化多不饱和脂肪酸（PUFAS）的抗炎环氧化物来调节细胞炎症，从而调节细胞炎症。在我们最近的研究中，我们确定了患者的脂质组谱失调，体内SEH活性升高（通过Oxylipin比率评估）。体内SEH标记物的增加持续在重量范围的AN中，进一步支持我们的假设，即EPHX2调节诱导促炎氧蛋白转移的SEH活性，因此SEH的升高不仅可能导致易感性，还会促进疾病和结果。检验该假设很重要，因为如果发现真正的SEH活性可能是预测疾病结果和指导治疗发展的有用生物标志物。 PUFA是Oxylipins的前体，因此PUFA可能会影响SEH在黄脂蛋白上的调节效率。患者以对肉类脂肪食品的强烈厌恶（富含ω-6 PUFA）而闻名，我们已经表明，患者的饮食ω-6：ω-3 PUFA比率降低了，这表明EPHX2 LIPIDOMIC途径的失调可能受到其PUFA摄入的影响。这是我们将检验以下假设：在患者中，由于SEH活性的增加，氧基汀的代谢受到干扰，并且扰动程度与PUFA有关，从而增加了食物厌恶，精神病理学的燃烧越高，结果不佳。在AIM 1中，我们将通过ω-6丰富的早餐挑战来测试EPHX2代谢组途径是否改变了厌食症。通过主张离体SEH活性来评估其与风险的关联，EPHX2基因的分子机制。我们还将表征EPHX2变体，以检查EPHX2非同义SNP（NSSNP）对离体SEH活性的影响。在AIM 3中，我们将利用粉刷前和美食后的心理病理特征和3个月的结果数据来评估SEH在疾病过程中的作用，并通过纵向设计来评估SEH的作用。这项研究之所以重要，是因为它将通过使用创新的餐食挑战方案来提供对发病机理的见解，该方案将揭示遗传和饮食因素如何协同工作以对风险，表型和结果的影响。这项研究的结果将揭示EPHX2影响A的机制，提高了我们预测疾病风险，监测疾病进展和治疗反应的能力，并为未来的营养和药物发展带来新的目标。