Novel role of very long chain fatty acids in the brain

描述（由申请人提供）：我们的实验室是第一个发现极长链脂肪酸-4（VLVL 4）的延长酶是一种负责极长链（VLC; eC26）脂肪酸生物合成的延长酶，发现极长链脂肪酸是更复杂的脂质分子（如鞘脂和磷脂酰胆碱）的组分。VL 4合成在视网膜和睾丸中发现的VLC多不饱和脂肪酸（VLC-PUFA），以及在皮肤和大脑中发现的VLC饱和脂肪酸（VLC-FA）。缺乏合成这些脂肪酸的能力的突变体NATVVL 4的杂合遗传导致常染色体显性Stargardt黄斑营养不良（STGD 3）中的青少年黄斑变性。具有STGD 3突变的纯合遗传（VL 4突变体/突变体）并因此不产生VLC-PUFA/VLC-FA的人发展鱼鳞病、癫痫、智力残疾和痉挛性四肢瘫痪，并在生命的最初几年内死亡。这建立了VLC 4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。我们的研究小组发现VLC-FA存在于大鼠脑内的鞘脂中。我们已经成功地建立了一个动物模型，重现了人类的状况。这种独特的动物模型将使我们能够研究VL 4和VLC-FA在神经细胞发育，结构和功能中的作用，这是一个新的和未探索的研究领域。我们的中心假设是VLC-FA在CNS中尚未描述的活动的发展/维持中起重要作用，并且VLC 4的突变和/或VLC-FA的缺失导致神经功能受损，表现为过度兴奋和癫痫发作。这一新的假设和本文提出的测试它的研究将使我们能够在理解神经发育和VL 4及其VLC-FA产物在大脑中的生物学作用方面开辟新的天地。我们提出以下三个具体目标来检验我们的假设。在这个R21申请中，我们提出了一系列实验，这些实验将为我们提供在第二年提交R 01申请所需的基本信息。1.检验CNS内VLC-FA缺失足以导致神经发育受损，进而导致神经功能障碍和癫痫发作的假设。2.为了表征CNS内的CD 34 VL 4及其产物的表达模式。3.目的：研究VLC 4突变和/或VLC-FA缺失介导的神经功能障碍的机制。

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.