Role of fatty acid metabolism in optic nerve hypoplasia

脂肪酸代谢在视神经发育不全中的作用

基本信息

批准号：
10522005
负责人：
Konark Mukherjee
金额：
$ 39.09万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522005
关键词：
3-Dimensional Alcohol abuse Alleles Animal Model Arachidonic Acids Astrocytes Axon Behavioral Assay Biochemical Blindness Bolus Infusion Brain Caliber Childhood Cholestasis Clinic Clinical Congenital Disorders Contrast Sensitivity Data Defect Developed Countries Development Diabetes Mellitus Diet Disease Docosahexaenoic Acids Electrophysiology (science)Essential Fatty Acids Etiology Fatty Acids Female Fetal Alcohol Syndrome Functional disorder Genes Histopathology Human Incidence Knockout Mice Knowledge Label Lactation Life Life Style Link Linoleic Acids Lipids Maintenance Maternal Age Measurement Measures Mediating Metabolic Metabolism Milk Mitochondria Mitochondrial Proteins Modeling Molecular Morphology Mothers Mus Mutant Strains Mice Mutation Nature Neuraxis Neuroglia Omega-6 Fatty Acids Optic Disk Disorder Optic Nerve Oral Pathogenesis Pathogenicity Pathology Pathway interactions Performance Peroxisomal Disorders Phospholipids Pituitary Gland Play Production Proteins Publishing Reactive Oxygen Species Retina Retinal Ganglion Cells Role Supplementation Techniques Testing Thinness Third Pregnancy Trimester Ultrastructural Pathology Vision Visual Visual system structure alcohol exposure astrogliosis awake axonopathy base dietary embryonic alcohol exposure experimental study fatty acid metabolism fatty acid oxidation in utero in vivo infancy innovation lipid metabolism liquid chromatography mass spectrometry maternal diabetes mitochondrial metabolism mother nutrition mouse model neonate neurodevelopment novel nutrient deprivation offspring optic nerve disorder oxidative damage postnatal pregnant prenatal protein expression protein function response tool uptake visual excitation

项目摘要

ABSTRACT Optic nerve hypoplasia (ONH) is a very common congenital optic nerve (ON) disorder and is the leading cause of childhood blindness in developed nations. ONH incidence has increased ~8-fold over the last two decades. ONH is characterized by a thin, underdeveloped ON that often results from secondary loss of retinal ganglion cells (RGCs). The most common prenatal determinants of ONH are a young primiparous mother, an unhealthy maternal lifestyle including alcohol abuse, and nutritional deprivation. We have developed and published murine models of ONH by manipulating the X-linked gene CASK, since CASK mutations in humans are associated with ONH. The ONH pathology of CASK mutant mice recapitulates human ONH, including the timing of pathology onset (after RGC development; i.e., secondary loss) and the non-progressive nature of the pathology. Biochemical experiments show that CASK interacts with metabolic proteins and modulates mitochondrial function. CASK deficiency leads to increased fatty acid oxidation and a deficit of the ω-6 fatty acid arachidonic acid (ARA) in the central nervous system (CNS). ARA deficiency is also observed in other conditions associated with ONH. We hypothesize that ONH results from an early ARA deficit, thus ONH can be exacerbated by perturbing brain ARA metabolism (via astrocyte dysfunction) and ameliorated by dietary ARA supplementation. During the third trimester, ARA is exclusively obtained from the mother; in neonates, brain ARA is also obtained from the diet until adequate enzymatic activity (conversion of the essential fatty acid linoleic acid into ARA) is reached. This post-neonatal shift in ARA acquisition from diet to synthesis may contribute to ONH’s non-progressive nature. In the CNS, fatty acid metabolism (including ARA uptake and production) occurs predominantly in astrocytes. In this proposal we plan to test our hypothesis in two independent ONH mouse models: 1) CASK(+/-) heterozygous knockout mice, and 2) a previously published fetal alcohol syndrome (FAS) mouse model. With these models, we will examine mitochondrial metabolism, oxidative damage and fatty acid metabolic defects in the retina, ON and brain. We will also quantify levels of two ω-fatty acids (docosahexaenoic acid and ARA), as well as phospholipids in the ON of both types of ONH mice. Next, we will genetically disrupt the function of astrocytes (crucial for brain ARA metabolism) in a CASK hypomorph ONH model by complete deletion of CASK in astrocytes. We will investigate if this manipulation exacerbates the metabolic defect and ONH as assessed both morphologically and functionally, using a visual behavioral assay and an innovative electrophysiological tool called Network Response to Visual Excitation (NeRVE). Finally, we will test if ARA supplementation ameliorates ONH in the two models described above. Our study is likely to identify ARA deficiency as the final common pathway that explains ONH’s association with nutritional deprivation, maternal diabetes, infantile cholestasis and FAS. Positive results from ARA supplementation will be readily translatable.

抽象的视神经性发育不全（ONH）是一种非常常见的先天性视神经（ON）疾病，是主要原因发达国家的儿童失明。在过去的二十年中，ONH的发病率增加了约8倍。 ONH的特征是薄而欠发达的特征，通常是由于残留神经节的继发性丧失而导致的细胞（RGC）。 ONH最常见的产前决定者是一个年轻的初次母亲，不健康孕产妇的生活方式，包括酗酒和营养剥夺。我们已经开发和出版了鼠通过操纵X连锁基因桶的ONH模型，因为人类的桶突变与 onh。木桶突变小鼠的ONH病理学概括了人类ONH，包括病理的时机发作（RGC发育后；即继发损失）和病理的非促进性。生化实验表明，木桶与代谢蛋白相互作用并调节线粒体功能。木桶缺乏会导致脂肪酸氧化增加和ω-6脂肪酸蛛网膜化的缺陷中枢神经系统（CNS）中的酸（ARA）。在其他相关条件下也观察到ARA缺乏症与Onh。我们假设ONH是由早期的ARA防御引起的，因此可以通过扰动脑ARA代谢（通过星形胶质细胞功能障碍），并通过饮食ARA改善补充。在三个月中，ARA专门从母亲那里获得。在新生儿，大脑还可以从饮食中获得ARA，直到足够的酶促活性（必需脂肪酸亚油酸的转化到达酸到ara）。从饮食到合成的ARA获取后，这种昆虫后转变可能有助于 Onh的非促进性质。在中枢神经系统中，发生脂肪酸代谢（包括ARA摄取和生产）主要在星形胶质细胞中。在此提案中，我们计划在两只独立的ONH小鼠中检验我们的假设模型：1）桶（+/-）杂合敲除小鼠，以及2）先前出版的胎儿酒精综合征（FAS）鼠标模型。使用这些模型，我们将检查线粒体代谢，氧化损伤和脂肪酸视网膜，大脑和大脑中的代谢缺陷。我们还将量化两种ω-脂肪酸的水平（docosahexaenoic）酸和ARA）以及两种类型的ONH小鼠的磷脂。接下来，我们将一般会破坏通过完整在星形胶质细胞中删除桶。我们将调查这种操作是否加剧了代谢缺陷和使用视觉行为分析和创新性，在形态和功能上评估了ONH。电生理工具称为网络对视觉激发（神经）的反应。最后，我们将测试ARA是否在上述两个模型中，补充可以改善ONH。我们的研究可能会识别ARA 缺乏症是最终的通用途径，解释了ONH与营养剥夺的关联，母亲糖尿病，基础设施胆汁淤积和FA。补充ARA的积极结果将很容易翻译。