SLOS and Neuronal Oxidative Stress

SLOS 和神经元氧化应激

• 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
• 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' 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

 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）是人体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。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的化合物更容易发生脂质过氧化反应。脂质过氧化与许多人类疾病相关，包括神经变性疾病，例如帕金森氏病、ALS、阿尔茨海默氏病和亨廷顿氏病。脂质过氧化过程中形成的许多化合物具有很强的生物活性，神经退行性变可能与这些有毒的过氧化产物有关。 一种影响20- 70，000人中1人的人类综合征，Smith-Lemli-Opitz综合征（SLOS），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中7-DHC浓度增加高达10，000倍。SLOS导致一系列大脑异常，这些患者还表现出智力迟钝和自闭症样症状。该提案的重点是SLOS中7-DHC积累的后果。我们的指导性假设是7-DHC的过氧化和7-DHC氧化固醇的形成在与SLOS相关的病理生理学中起着重要作用。 该假说还指出，7-DHC的积累，无论是通过遗传倾向还是通过暴露于破坏胆固醇生物合成的小分子，都可能对健康产生影响。这将我们的研究集中在下一个资助期，以评估7-DHC氧固醇在细胞和组织中的分布和代谢，定义与7-DHC氧固醇病理学相关的机制，设计降低体内7-DHC和/或其氧固醇的流体和组织水平的策略，并准确测量受影响的SLOS中的固醇和氧固醇水平，SLOS载体和对照人血浆，以便进行治疗研究。我们断言，准确测量细胞、体液和组织中7-DHC及其氧固醇的方法，以及理解和调节与这种固醇相关的病理生理学的策略，将对许多健康问题产生影响，这些问题广泛地从固醇生物合成的错误到药物毒性和暴露。 脂质过氧化经常与神经退行性疾病有关，本研究与公共卫生的相关性是过氧化的化学和生物学基础研究及其抑制与神经退行性疾病（包括破坏性综合征SLOS）的联系。