Investigating the Mechanism of Optic Nerve disorders associated with Down Syndrome

研究与唐氏综合症相关的视神经疾病的机制

基本信息

批准号：
10658120
负责人：
Konark Mukherjee
金额：
$ 147.51万
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：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658120
关键词：
3-Dimensional Acids Arachidonic Acids Autopsy Axon Behavior Behavioral Biochemical Bioenergetics Bolus Infusion Brain Ca(2+)-Calmodulin Dependent Protein Kinase Calmodulin Cardiolipins Central Nervous System Child Childhood Cholestasis Chromosome abnormality Clinic Clinical Contrast Sensitivity Data Defect Developed Countries Development Diabetes Mellitus Diagnosis Diameter Diet Dietary Supplementation Docosahexaenoic Acids Down Syndrome Electrophysiology (science)Exhibits FABP3 gene Face Fatty Acids Functional disorder Gene Expression General Population Generations Genes Genetic Diseases Glucose Human Imaging Techniques Individual Investigation Label Lactation Learning Disabilities Lecithin Legal Blindness Life Lipids Liquid Chromatography Literature Measures Metabolic Metabolism Methods Microcephaly Milk Mitochondria Modeling Mus Mutant Strains Mice Mutation Names Nature Omega-6 Fatty Acids Optic Disk Optic Nerve Oral Pathogenesis Pathology Patients Performance Phosphatidylethanolamine Phosphatidylinositols Phosphatidylserines Phospholipids Plasmalogens Play Polyunsaturated Fatty Acids Prevalence Production Protein-Serine-Threonine Kinases Quality of life Reactive Oxygen Species Reporting Respiration Retina Retinal Ganglion Cells Rodent Role Scanning Electron Microscopy Secondary to Sensory Supplementation Techniques Testing Thinness Third Pregnancy Trimester Tracer United States Vision Visual Visual Acuity Visual System Visual evoked cortical potential alcohol exposure awake behavior test brain dysfunction clinical practice clinical translation density dietary experimental study fatty acid metabolism fatty acid oxidation hearing impairment improved in utero in vivo infancy insight legally blind lipid metabolism minimal risk mitochondrial dysfunction mitochondrial metabolism morphometry mouse Ts65Dn mouse model mutant mouse model neurodevelopment neurological pathology non-genetic novel nutrient deprivation offspring optic nerve disorder optical disc oxidation oxidative damage postnatal pregnant response retinogeniculate tandem mass spectrometry three-dimensional visualization visual excitation visual processing

项目摘要

PROJECT ABSTRACT The prevalence of optic nerve hypoplasia (ONH) among individuals with Down syndrome (DS) is more than ~100 folds higher than in the general population. ONH is characterized by a thin, underdeveloped optic nerve that often results from secondary loss of retinal ganglion cells (RGCs) and is the leading cause of childhood legal blindness in developed nations. We have developed a murine model of ONH by manipulating the CASK (calcium/calmodulin dependent serine protein kinase) gene. The ONH pathology of CASK mutant mice recapitulates many aspects of human ONH, including the timing of the onset of pathology (after RGC development, i.e., secondary loss) and the non-progressive nature of the pathology. In addition to ONH, DS and pathology associated with CASK mutation share other similarities such as microcephaly. Biochemical experiments suggest that similar to DS, CASK mutation alters mitochondrial function, resulting in aberrant fatty acid metabolism. We have uncovered a deficiency of the ω-6 polyunsaturated fatty acid arachidonic acid (ARA) in the central nervous system (CNS) of CASK mutant mice. A specific reduction of ARA-containing lipids has been also reported in postmortem human DS brains. In both CASK mutant mice and the DS murine model visual contrast sensitivity is reduced. Based on the literature and our observations, we hypothesize that ARA deficiency in the optic nerve (ON) leads to ONH in DS. If this hypothesis is correct, dietary ARA supplementation could ameliorate ONH in DS. In this proposal, we plan to use two independent murine DS models (Ts65Dn and DP16 mice) to investigate retinal circuit and retinogeniculate connectivity using appropriate markers and tracers along with imaging techniques. Three-dimensional ultrastructural morphometry of the ON in DS murine models will be performed using serial block-face scanning electron microscopy (SBFSEM). Behavioral experiments will document visual defects. Visual circuit function will be evaluated with a novel in vivo electrophysiological technique we have named Network Response to Visual Excitation (NeRVE), a method that will be applicable beyond this proposal to better understand rodent vision processing. Mitochondrial metabolism, reactive oxygen species generation, oxidative damage, and fatty acid metabolic defects in the retina, optic nerve and brain of two independent DS mouse models will be measured. We will also quantify the levels of two ω- polyunsaturated fatty acids (docosahexaenoic acid and ARA), as well as phospholipids, in the ON of both types of DS mice. Finally, we will test if ARA supplementation ameliorates known defects in visual acuity and contrast sensitivity in these two DS mouse models. Our study is likely to provide data on DS pathobiology and provide a clear mechanism for the co-occurrence of ONH in DS. Furthermore, promising results from our ARA supplementation study would be immediately translatable into clinical practice for the amelioration of ONH in individuals with DS.

项目摘要唐氏综合症患者（DS）中视神经发育不全（ONH）的患病率超过100 折叠高于一般人群。 ONH的特征是薄而欠发达的视神经通常是由于视网膜神经节细胞（RGC）的继发性丧失而导致的，并且是儿童时期合法的主要原因发达国家的失明。我们已经通过操纵桶开发了ONH的鼠模型（钙/钙调蛋白依赖性丝氨酸蛋白激酶）基因。桶形突变小鼠的病理学概括了人类ONH的许多方面，包括病理发作的时间（RGC之后发展，即继发性损失）和病理的非促进性。除了ONH，DS和与桶突变相关的病理具有其他相似性，例如小头畸形。生化实验表明，类似于DS，CASK突变会改变线粒体功能，导致异常脂肪酸代谢。我们发现了ω-6多不饱和脂肪酸花生四烯酸（ARA）的缺陷在桶突变小鼠的中枢神经系统（CNS）中。特定的含ARA脂质的降低具有还报道了我们在尸体后的DS大脑中的报道。在CASK突变小鼠和DS鼠模型的视觉中对比度灵敏度降低。根据文献和我们的观察，我们假设ARA 视神经（ON）缺乏导致DS中的ONH。如果此假设正确，则饮食ARA 补充可以改善DS。在此提案中，我们计划使用两个独立的鼠DS 模型（TS65DN和DP16小鼠）使用适当的标记和示踪剂以及成像技术。 ON的三维超微结构形态学在DS鼠模型中，将使用串行块面扫描电子显微镜（SBFSEM）进行。行为实验将记录视觉缺陷。视觉电路函数将通过新颖的体内评估电生理技术我们将网络响应对视觉激发（神经）的响应命名，这种方法是将不仅适用此提案，以更好地了解啮齿动物的视力处理。线粒体代谢，电性氧的产生，氧化物损伤和视网膜的脂肪酸代谢缺陷，视神经将测量两个独立的DS小鼠模型的大脑。我们还将量化两个两个ω-的水平两种类型的磷酸脂肪酸（二十二碳六烯酸和ARA）以及磷脂 DS小鼠。最后，我们将测试补充ARA是否可以改善视力和对比度的已知缺陷这两个DS小鼠模型中的灵敏度。我们的研究可能会提供有关DS病理生物学的数据，并提供 ds中ONH共发生的清晰机制。此外，我们的ARA有希望的结果补充研究将立即转化为临床实践，以改善ONH 患有DS的人。