SLOS and Neuronal Oxidative Stress

SLOS 和神经元氧化应激

基本信息

批准号：
8150360
负责人：
Ned Allen Porter
金额：
$ 31.08万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-27 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8150360
关键词：
7-dehydrocholesterol 7-dehydrocholesterol reductase Acetylcysteine Affect Alzheimer&apos s Disease Anabolism Animals Antioxidants Astrocytes Autistic Disorder Biological Biological Assay Biological Markers Biology Brain Cell Culture Techniques Cell Line Cell Proliferation Cell Survival Cells Cerebrospinal Fluid Characteristics Chemistry Cholecalciferol Cholesterol Cholesterol Homeostasis Data Defect Development Disease Embryo Enzymes Exhibits Fatty Acids Fibroblasts Free Radicals Gene Expression Growth Hereditary Disease High Pressure Liquid Chromatography Human Human Biology Huntington Disease Image Imaging Techniques In Vitro Individual Isotopes Lead Light Link Lipid Peroxidation Lipids Liquid substance Maps Measurable Mental Retardation Metabolic Diseases Metabolism Methods Modeling Molecular Morphology Mus Mutation National Institute of Child Health and Human Development Neonatal Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurons Organ Outcome Oxidative Stress Oxygen Parkinson Disease Pathway interactions Patients Plasma Poison Process Property Public Health Publishing Research Rodent Rodent Model Sampling Series Skin Smith-Lemli-Opitz Syndrome Source Staging Sterols Symptoms Syndrome System Testing Tissues Tocopherols Toxic effect Tritium United States National Institutes of Health Urine Vitamin E Work ascorbate chemical synthesis cholesterol biosynthesis fetal genetically modified cells human disease human tissue hydroxypyridine in vivo ion mobility lipid peroxidation inhibitor material transfer agreement member mouse model neuron development neuronal survival novel oxidation peroxidation public health relevance research study small molecule tissue culture

项目摘要

DESCRIPTION (provided by applicant): 7-Dehydrocholesterol (7-DHC) is an important lipid in human biology. It is the immediate biosynthetic precursor of cholesterol and it is also a precursor to vitamin D3. Very recent discoveries indicate that 7-DHC is very prone to undergo free radical chain oxidation with molecular oxygen, i.e. lipid peroxidation. Indeed, 7- DHC's reactivity makes it more susceptible to lipid peroxidation than nearly any other known compound. Lipid peroxidation is associated with many human diseases, including neurodegenerative disorders such as Parkinson's, ALS, Alzheimer's and Huntington's diseases. Many of the compounds formed during lipid peroxidation have potent biological activities and neurodegeneration may be associated with these toxic peroxidation products. A human syndrome affecting 1 in 10-30,000 individuals, Smith-Lemli-Opitz Syndrome (SLOS), is caused by a defect in the enzyme (Dhcr-7) that promotes the last step of cholesterol biosynthesis. This defect results in an increase by up to 10,000-fold of 7-DHC concentrations in individuals suffering from this syndrome. SLOS causes a range of brain abnormalities and these patients also exhibit mental retardation and autism-like symptoms. This proposal is focused on the consequences of the accumulation of 7-DHC in SLOS. A guiding hypothesis is that 7-DHC and its peroxidation metabolites are detrimental to neuronal function. The hypothesis also states that accumulation of 7-DHC and its peroxidation-derived byproducts leads to changes in the growth and function of neurons, the consequences being the devastating abnormalities observed in these individuals. The peroxidation products of 7-DHC have been isolated, purified and fully characterized. Methods will be developed to determine if these peroxidation products or their metabolites are observed as biomarkers in tissues and cells having elevated levels of 7-DHC. The systems studied will include three SLOS mouse models, neuronal cells that are genetically engineered to have high levels of 7-DHC, skin-cells (fibroblasts) from seven SLOS patients and plasma, urine and cerebral spinal fluid from patient samples by Dr. Forbes Porter at the NIH/NICHD. Another major theme of the research is to assess the biological consequences resulting from exposure of a cell or animal to 7-DHC peroxidation products. The effect of peroxidation products on neuronal cell viability, morphology and gene expression will be assessed and finally, an effort will be initiated to find small molecule inhibitors of lipid peroxidation (antioxidants) that protect cells and reverse the phenotypic characteristics of SLOS rodent models. Lipid peroxidation is frequently linked to neurodegenerative disorders and the relevance of this research to public health is the linkage of the fundamental studies in the chemistry and biology of peroxidation and its inhibition proposed here to neurodegenerative disorders, including a devastating syndrome, SLOS. PUBLIC HEALTH RELEVANCE: Smith-Lemli-Opitz syndrome (SLOS) is a devastating neurodevelopmental metabolic disorder caused by a defect in cholesterol biosynthesis that leads to a build up of toxic oxysterol compounds. Establishing assays for the toxic compounds in human fluids and understanding their fundamental neurobiology will shed light on SLOS and lead to therapies for this disorder and others that have altered cholesterol metabolism.

描述（由申请人提供）：7-脱氢胆固醇（7-DHC）是人类生物学中的重要脂质。它是胆固醇的直接生物合成前体，也是维生素 D3 的前体。最近的发现表明，7-DHC 很容易与分子氧发生自由基链氧化，即脂质过氧化。事实上，7-DHC 的反应性使其比几乎任何其他已知化合物更容易受到脂质过氧化的影响。脂质过氧化与许多人类疾病有关，包括神经退行性疾病，如帕金森病、肌萎缩侧索硬化症、阿尔茨海默病和亨廷顿病。脂质过氧化过程中形成的许多化合物具有有效的生物活性，神经变性可能与这些有毒的过氧化产物有关。史密斯-莱姆利-奥皮茨综合症 (SLOS) 是一种影响十分之一的人类综合症，是由促进胆固醇生物合成最后一步的酶 (Dhcr-7) 缺陷引起的。这种缺陷导致患有这种综合征的个体体内 7-DHC 浓度增加多达 10,000 倍。 SLOS 会导致一系列大脑异常，这些患者还表现出智力低下和自闭症样症状。该提案的重点是 7-DHC 在 SLOS 中积累的后果。一个指导性假设是 7-DHC 及其过氧化代谢物对神经元功能有害。该假说还指出，7-DHC 及其过氧化副产物的积累会导致神经元生长和功能的变化，其后果是在这些个体中观察到的破坏性异常。 7-DHC 的过氧化产物已被分离、纯化并充分表征。将开发方法来确定这些过氧化产物或其代谢物是否被观察为7-DHC水平升高的组织和细胞中的生物标志物。研究的系统将包括三个 SLOS 小鼠模型、经过基因工程改造具有高水平 7-DHC 的神经元细胞、来自七名 SLOS 患者的皮肤细胞（成纤维细胞）以及福布斯博士从患者样本中提取的血浆、尿液和脑脊液NIH/NICHD 的波特。该研究的另一个主要主题是评估细胞或动物接触 7-DHC 过氧化产物所产生的生物学后果。将评估过氧化产物对神经元细胞活力、形态和基因表达的影响，最后，将开始努力寻找脂质过氧化的小分子抑制剂（抗氧化剂），以保护细胞并逆转 SLOS 啮齿动物模型的表型特征。脂质过氧化经常与神经退行性疾病相关，这项研究与公共健康的相关性是将过氧化的化学和生物学基础研究及其此处提出的抑制与神经退行性疾病（包括破坏性综合征，SLOS）联系起来。公共卫生相关性：Smith-Lemli-Opitz 综合征 (SLOS) 是一种破坏性的神经发育代谢紊乱，由胆固醇生物合成缺陷引起，导致有毒氧甾醇化合物的积累。对人体体液中的有毒化合物进行检测并了解其基本神经生物学将有助于阐明 SLOS，并为这种疾病和其他改变胆固醇代谢的疾病提供治疗方法。