SLOS and Neuronal Oxidative Stress

SLOS 和神经元氧化应激

基本信息

批准号：
9198250
负责人：
Ned Allen Porter
金额：
$ 43.28万
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 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198250
关键词：
7-dehydrocholesterol 7-dehydrocholesterol reductase AY9944 Affect Alzheimer&apos s Disease Antioxidants Autistic Disorder Biological Biological Assay Biology Brain Cell Culture Techniques Cell Line Cells Chemistry Cholecalciferol Cholesterol Cholesterol Homeostasis Collection Complex Control Groups Defect Desmosterol Development Disease Distributional Activity Drug Exposure Drug toxicity Enzymes Epoxy Compounds Exhibits Exposure to Fibroblasts Follow-Up Studies Free Radicals Frequencies Functional disorder Gene Expression Genetic Grant Health Hereditary Disease Human Human Biology Huntington Disease Individual Infant Isotopes Knockout Mice Laboratories Lanosterol Lead Libraries Light Link Lipid Peroxidation Lipid Peroxides Lipids Liquid substance Measurable Measures Mental Retardation Metabolic Metabolic Diseases Metabolism Methods Modeling Modification Molecular Mutant Strains Mice Mutation Nerve Degeneration Neurobiology Neurodegenerative Disorders Neuronal Differentiation Neurons Nuclear Receptors Organ Oxidative Stress Oxygen Parkinson Disease Pathology Pathway interactions Patients Peroxides Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phenotype Plasma Play Process Proteins Protocols documentation Public Health Rattus Records Research Rodent Role Sampling Smith-Lemli-Opitz Syndrome Standard Preparations Sterol Biosynthesis Pathway Sterols Symptoms Syndrome Therapeutic Studies Tissues Treatment-related toxicity Variant Work adduct brain abnormalities cholesterol biosynthesis congenital anomaly human disease in vivo lipid biosynthesis mortality mouse model neuroblastoma cell oxidation peroxidation postnatal public health relevance screening small molecule

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 20-70,000 individuals, Smith-Lemli-Opitz Syndrome (SLOS), is caused by a defect in the enzyme (Dhcr7) 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. Our guiding hypothesis is that the peroxidation of 7-DHC and the formation of 7-DHC oxysterols plays an important role in the pathophysiology associated with SLOS. The hypothesis also states that accumulation of 7-DHC, either by genetic disposition or by exposure to small molecules that disrupt cholesterol biosynthesis can have health consequences. This focuses our studies in the next grant period to assessing the distribution and metabolism of 7-DHC oxysterols in cells and tissues, defining mechanisms associated with 7-DHC oxysterol pathology, devising strategies to reduce fluid and tissue levels of 7-DHC and/or its oxysterols in vivo, and accurately measuring levels of sterols and oxysterols in SLOS affected, SLOS carrier and control human plasmas in order to enable therapeutic studies. We assert that methods to accurately measure 7-DHC and its oxysterols in cells, fluids and tissues and strategies to understand and moderate the pathophysiology associated with this sterol will have an impact on a number of health issues ranging broadly from errors in sterol biosynthesis to drug toxicity and exposures. Lipid peroxidation is frequentl 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.

描述（由申请人提供）： 7-脱氢胆固醇 (7-DHC) 是人类生物学中的一种重要脂质，它是胆固醇的直接生物合成前体，也是维生素 D3 的前体。很容易发生分子氧的自由基链氧化，即脂质过氧化。事实上，7-DHC 的反应性使其比脂质过氧化更容易发生。几乎任何其他已知的化合物都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。许多脂质过氧化过程中形成的化合物具有有效的生物活性，而神经退行性疾病可能与这些有毒的过氧化有关。史密斯-莱姆利-奥皮茨综合症 (SLOS) 是一种影响 20-70,000 分之一的人类综合症，是由酶缺陷引起的。 (Dhcr7) 促进胆固醇生物合成的最后一步，这种缺陷导致患有这种综合征的个体的 7-DHC 浓度增加多达 10,000 倍，导致一系列大脑异常，这些患者还表现出智力低下。该提案的重点是 7-DHC 在 SLOS 中积累的后果，我们的指导假设是 7-DHC 的过氧化和形成。 7-DHC 氧化甾醇在与 SLOS 相关的病理生理学中发挥着重要作用。该假设还指出，通过遗传倾向或通过接触破坏胆固醇生物合成的小分子而积累的 7-DHC 可能会产生健康后果。下一个资助期将评估 7-DHC 氧甾醇在细胞和组织中的分布和代谢，定义与 7-DHC 氧甾醇病理学相关的机制，制定策略以降低体液和组织中 7-DHC 氧甾醇的水平7-DHC 和/或其氧化甾醇在体内，并准确测量受 SLOS 影响的、SLOS 载体和对照人血浆中的甾醇和氧化甾醇水平，以便能够准确测量 7-DHC 及其氧化甾醇的治疗研究。细胞、体液和组织以及了解和调节与该甾醇相关的病理生理学的策略将对许多健康问题产生影响，范围广泛，包括甾醇生物合成的错误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）联系起来。，SLOS。