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：
10707368
负责人：
Konark Mukherjee
金额：
$ 39.07万
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/10707368
关键词：
3-Dimensional Acids Alcohol abuse Alleles Animal Model Arachidonic Acids Astrocytes Axon Behavioral Assay Biochemical Blindness Bolus Infusion Brain Central Nervous System Childhood Cholestasis Clinic Clinical Congenital Disorders Contrast Sensitivity Data Defect Developed Countries Development Diabetes Mellitus Diameter Diet Disease Docosahexaenoic Acids Electrophysiology (science)Essential Fatty Acids Etiology Fatty Acids Female Fetal Alcohol Syndrome Functional disorder Genes Heterozygote 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 Neonatal 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 alcohol exposure astrogliosis awake axonopathy 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.

抽象的视神经发育不全 (ONH) 是一种非常常见的先天性视神经 (ON) 疾病，也是导致视神经发育不良的主要原因过去 20 年来，发达国家儿童失明率增加了约 8 倍。 ONH 的特点是视网膜较薄且不发达，通常是由于视网膜神经节继发性丧失所致 ONH 最常见的产前决定因素是年轻的初产母亲、不健康的人。母亲的生活方式，包括酗酒和营养缺乏，我们已经开发并发表了小鼠。通过操纵 X 连锁基因 CASK 来建立 ONH 模型，因为人类的 CASK 突变与 CASK 突变小鼠的 ONH 病理学概括了人类 ONH，包括病理学的时间。发病（RGC 发育后；即继发性丧失）和病理学的非进展性。生化实验表明，CASK 与代谢蛋白相互作用并调节线粒体 CASK 缺乏会导致脂肪酸氧化增加和 ω-6 脂肪酸花生四烯酸缺乏。在其他相关疾病中也观察到中枢神经系统 (CNS) 中的 ARA 缺乏。我们欺负 ONH 是早期 ARA 赤字的结果，因此 ONH 可能会因早期 ARA 赤字而加剧。干扰大脑 ARA 代谢（通过星形胶质细胞功能障碍）并通过膳食 ARA 改善在妊娠晚期，ARA 只从母亲的大脑中获取； ARA 也可以从饮食中获得，直到有足够的酶活性（必需脂肪酸亚油酸的转化）这种新生儿后 ARA 获取从饮食到合成的转变可能有助于实现。 ONH 的非渐进性在中枢神经系统中发生脂肪酸代谢（包括 ARA 的摄取和产生）。主要是在星形胶质细胞中，我们计划在两只独立的 ONH 小鼠中检验我们的假设。模型：1) CASK(+/-) 杂合基因敲除小鼠，2) 先前发表的胎儿酒精综合症 (FAS) 通过这些模型，我们将检查线粒体代谢、氧化损伤和脂肪酸。视网膜、ON 和大脑的代谢缺陷我们还将量化两种 ω-脂肪酸（二十二碳六烯酸）的水平。酸和 ARA），以及两种类型 ONH 小鼠 ON 中的磷脂接下来，我们将进行基因破坏。星形胶质细胞（对大脑 ARA 代谢至关重要）在 CASK 亚型 ONH 模型中的功能我们将研究星形胶质细胞中 CASK 的缺失是否会加剧代谢缺陷和使用视觉行为分析和创新方法对 ONH 进行形态学和功能性评估称为视觉兴奋网络响应 (NeRVE) 的电生理学工具最后，我们将测试 ARA。补充剂可改善上述两种模型中的 ONH，我们的研究很可能识别出 ARA。缺乏症是解释 ONH 与营养缺乏、孕产妇糖尿病、婴儿胆汁淤积和 FAS 的积极结果很容易转化。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novel insights into the nervous system affected by prolonged hyperglycemia.

对长期高血糖影响的神经系统的新见解。

DOI：
发表时间：
2023-08
期刊：
影响因子：
0
作者：
Zglejc;Mukherjee, Konark;Korytko, Agnieszka;Lewczuk, Bogdan;Pomianowski, Andrzej;Wojtkiewicz, Joanna;Banach, Marta;Załęcki, Michał;Nowicka, Natalia;Jarosławska, Julia;Kordas, Bernard;Wąsowicz, Krzysztof;Juranek, Judyta K
通讯作者：
Juranek, Judyta K