Novel role of very long chain fatty acids in the brain

超长链脂肪酸在大脑中的新作用

基本信息

批准号：
8807392
负责人：
ROBERT E ANDERSON
金额：
$ 21.98万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8807392
关键词：
Adolescent Age Anabolism Animal Model Area Biochemical Biochemical Reaction Biological Biological Assay Birth Brain Case Study Ceramides Cessation of life Child Complex Dehydration Development Disease Electrophysiology (science)Fatty Acids Fluorescence Microscopy Functional disorder Genes Genetically Engineered Mouse Heart Hippocampus (Brain)Hour Human Ichthyoses Individual Inherited Intellectual functioning disability Keratin Laboratories Lead Lecithin Life Link Lipids Liver Macular degeneration Maintenance Mediating Metabolism Mus Mutation Neurodegenerative Disorders Neurons Neurophysiology - biologic function Organ Pattern Phenotype Play Polyunsaturated Fatty Acids Rattus Reporting Research Retina Retinal Degeneration Role Saturated Fatty Acids Seizures Series Skin Slice Spastic Tetraplegia Sphingolipids Stargardt&apos s disease Structure Synapses Testing Testis Tonic - clonic seizures Transgenic Mice Very Long Chain Fatty Acid Vision brain cell enhanced green fluorescent protein glucose uptake human disease involucrin knockout animal metabolomics mouse model mutant myelination neurodevelopment neuromechanism neuropathology novel prevent promoter public health relevance pup relating to nervous system research study

项目摘要

DESCRIPTION (provided by applicant): Our lab was the first to discover that ELOngation of Very Long chain fatty acids-4 (ELOVL4) is an elongase responsible for biosynthesis of very long chain (VLC; eC26) fatty acids that are found as components of more complex lipid molecules such as sphingolipids and phosphatidylcholine. ELOVL4 synthesizes the VLC polyunsaturated fatty acids (VLC-PUFA) found in retina and testes, and VLC saturated fatty acids (VLC-FA) in skin and brain. Heterozygous inheritance of mutant ELOVL4, which lacks the ability to synthesize these fatty acids, causes juvenile macular degeneration in autosomal dominant Stargardt's macular dystrophy (STGD3). Humans with homozygous inheritance of the STGD3 mutation (ELOVL4 mutant/mutant), and thus make no VLC- PUFA/VLC-FA, develop ichthyosis, seizures, intellectual disability, and spastic quadriplegia, and die within the first few years of ife. This establishes a causal link between the mutation in ELOVL4 to a neurodegenerative disease; other than that, nothing is known about the role and importance of VLC-FA in the brain. Our group showed that VLC-FA are in sphingolipids in the rat brain. We have successfully generated an animal model that recapitulates the human condition. This unique animal model will enable us to study the role of ELOVL4 and VLC-FA in neural cell development, structure and function, which is a novel and unexplored area of research. Our central hypothesis is that VLC-FA play an important role in the development/maintenance of as yet undescribed activities in the CNS and that mutations in ELOVL4 and/or loss of VLC-FA lead to impaired neural function, evident by hyper-excitability and seizures. This novel hypothesis and the studies proposed herein to test it will allow us to break new ground in understanding neural development and the biological role of ELOVL4 and its VLC-FA products in the brain. We propose the following three specific aims to test our hypothesis. In this R21 application, we propose a series of experiments that will provide us with the basic information we will need to submit an R01 application in the second year. 1. To test the hypothesis that a loss of VLC-FA within the CNS is sufficient to cause impaired neural development leading to neural dysfunction and seizures. 2. To characterize the expression pattern of ELOVL4 and its products within the CNS. 3. To determine the mechanism of neural dysfunction mediated by mutations in ELOVL4 and/or loss of VLC-FA.

描述（由申请人提供）：我们的实验室是第一个发现非常长的链脂肪酸-4（ElOVL4）的伸长率是一种伸长酶，负责长链（VLC; EC26）脂肪酸的生物合成，这些脂肪酸被发现是更复杂的脂质分子的成分，例如sphinglocipids和phhosphathopids和phhosphaticylchatipidylchatipidylchatipidylcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholcholchol in。 ELOVL4合成了在视网膜和睾丸中发现的VLC多不饱和脂肪酸（VLC-PUFA），并在皮肤和大脑中合成VLC饱和脂肪酸（VLC-FA）。突变体Elovl4的杂合遗传缺乏合成这些脂肪酸的能力，会导致常染色体显性stargardt stargardt的黄斑营养不良症（STGD3）引起少年黄斑变性。具有STGD3突变（ELOVL4突变/突变体）纯合遗传的人类，因此不产生vlcpufa/vlc-fa，会发展出疾病，癫痫发作，智力残疾和痉挛性四肢瘫痪，并在IFE的头几年内死亡。这建立了ELOVL4突变与神经退行性疾病之间的因果关系。除此之外，对VLC-FA在大脑中的作用和重要性一无所知。我们的小组表明，VLC-FA在大鼠大脑的鞘脂中。我们成功地生成了一种概括人类状况的动物模型。这种独特的动物模型将使我们能够研究Elovl4和VLC-FA在神经细胞发育，结构和功能中的作用，这是一个新颖且未开发的研究领域。我们的核心假设是，VLC-FA在中枢神经系统中未描述的活动的开发/维持中起着重要作用，并且ELOVL4和/或VLC-FA丢失的突变导致神经功能受损，这通过高度启发性和癫痫发作证明。这一新颖的假设和本文提出的研究将使我们能够在理解神经发育以及Elovl4及其VLC-FA产品在大脑中的生物学作用方面取得新的基础。我们提出以下三个特定旨在检验我们的假设的特定旨在。在此R21应用程序中，我们提出了一系列实验，这些实验将为我们提供第二年提交R01申请的基本信息。 1。检验以下假设：中枢神经系统内VLC-FA的损失足以引起神经发育受损，导致神经功能障碍和癫痫发作。 2。表征CNS内ElOVL4及其产物的表达模式。 3。确定通过ELOVL4突变和/或VLC-FA丢失的神经功能障碍的机制。