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

• 批准号: 9912191
• 负责人: Pei-an (Betty) Shih
• 金额: $ 40.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-21 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912191
• 关键词: Affect; Anorexia Nervosa; Anti-Inflammatory Agents; Arachidonic Acids; Base of the Brain; Biochemistry; Biological Assay; Biological Markers; Cessation of life; Chronic; Data; Development; Diet; Dietary Factors; Disease; Disease Outcome; Disease Progression; Emaciation; Enzymes; Epoxide hydrolase; Epoxy Compounds; Exposure to; Fasting; Food; Food Aversion; Functional disorder; Future; Genes; Genetic; Glycols; Health; Heritability; Inflammation; Inflammatory; Intake; Intervention; Knowledge; Lead; Link; Lipids; Measures; Meat; Mental Health; Messenger RNA; Metabolism; Molecular; Monitor; Morbidity - disease rate; Nutraceutical; Omega-3 Fatty Acids; Omega-6 Fatty Acids; 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; 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; multiple omics; non-genetic; public health relevance; restrictive eating; risk variant; therapy development; trait; treatment response

 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（由申请人提供）：神经性厌食症（AN）的特点是严重限制饮食和消瘦，发病率、慢性率和死亡率都很高，目前的治疗方法复发率和复发率很高，因此开发新的和改进的疗法具有很高的难度。虽然 AN 具有高度遗传性，但要优先考虑心理和公共卫生。 由于缺乏关于基因如何与非遗传风险因素相互作用的足够知识，我们对 AN 病理生理学的风险基因和相关机制尚未取得成功。将使用膳食挑战研究设计来检查可溶性环氧化物水解酶 (sEH)（AN 易感基因 EPHX2 的基因产物）如何影响 AN 精神病理学和结果，以阐明 EPHX2 的机制sEH 是影响生物活性代谢物（称为氧脂质）的脂质信号传导功能的关键酶，它通过将多不饱和脂肪酸 (PUFA) 的抗炎环氧化物转化为促炎氧脂质来调节细胞炎症。 AN 患者的脂质组学失调和体内 sEH 活性升高（通过氧脂质比率评估）体内 sEH 标记物的增加持续存在。体重恢复的 AN，进一步支持了我们的假设，即 EPHX2 调节 sEH 活性，从而诱导促炎性氧脂素转变，因此 sEH 可能不仅有助于 AN 易感性​​，而且还有助于检验这一升高的假设，因为如果发现正确， sEH 活性可以作为预测疾病结果和指导治疗开发的有用生物标志物。PUFA 是氧脂素的前体，因此 PUFA 可能会影响 sEH 的调节效率。 AN 患者因强烈厌恶肉类脂肪食物（富含 ω-6 PUFA）而闻名，我们已经证明 AN 患者饮食中 ω-6:ω-3 PUFA 比例下降，这表明 AN 患者的饮食失调。 AN 中的 EPHX2 脂质组学途径可能受到其 PUFA 摄入量的影响，因此，我们将检验以下假设：在 AN 患者中，氧脂素的代谢由于 sEH 活性的增加而受到干扰，且扰动的程度也不同。在目标 1 中，我们将测试富含 ω-6 的早餐挑战是否会改变神经性厌食症的 EPHX2 代谢途径。我们将通过测定离体 sEH 活性来强调 EPHX2 基因的基本生物化学和分子机制，以评估其与 AN 风险的关联。检查 EPHX2 非同义 SNP (nsSNP) 对离体 sEH 活性的影响 在目标 3 中，我们将利用餐前和餐后 AN 精神病理特征和 3 个月的结果数据来评估 sEH 在 AN 疾病中的作用。这项研究意义重大，因为它将通过使用创新的膳食挑战方案来深入了解 AN 的发病机制，揭示遗传和饮食因素如何协同作用。对 AN 风险、表型和结果产生影响 这项研究的结果将揭示 EPHX2 影响 AN 的机制，提高我们预测疾病风险、监测疾病进展和治疗反应的能力，并为未来的营养保健品和药物找到新的目标。事态发展。