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（由适用提供）：7-脱氢胆固醇（7-DHC）是人类生物学的重要脂质。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非常容易用分子氧（即脂质过氧化）进行自由基链氧化。实际上，7-DHC的反应性使其比几乎任何已知化合物都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，包括帕金森氏症，ALS，阿尔茨海默氏症和亨廷顿疾病等神经退行性疾病。脂质过氧化过程中形成的许多化合物具有潜在的生物学活性，神经退行性可能与这些有毒的过氧化产物有关。一种影响20-70,000个个体中1个史密斯 - 莱姆利 - 奥皮茨综合征（SLO）的人类综合征是由促进胆固醇生物合成最后一步的酶（DHCR7）中的缺陷引起的。这种缺陷导致患有该综合征的个体的7-DHC浓度增加了10,000倍。 SLO会引起一系列脑部异常，这些患者还暴露了智力低下和类似自闭症的症状。该提案的重点是SLO中7-DHC积累的后果。我们的指导假设是，7-DHC的过氧化和7-DHC氧酚的形成在与SLOS相关的病理生理学中起重要作用。该假设还指出，通过遗传处置或暴露于破坏胆固醇生物合成的小分子可能会产生健康后果，从而积累了7-DHC。这将我们的研究重点放在下一个赠款期间，以评估细胞和组织中7-DHC氧蛋白酶的分布和代谢，定义与7-DHC氧蛋白酶病理学相关的机制，制定策略以降低7-DHC的液体和组织水平和/或ITS氧蛋白酶在体内和固定酚的水平，并在固醇中的水平和氧化酚的水平，从而降低了固醇的水平，并在固醇中的水平进行了影响。启用治疗研究。我们断言，在细胞，液体和组织中准确测量7-DHC及其氧蛋白酶的方法以及与该固醇相关的病理生理学理解和调节的策略将对许多健康问题产生影响，从固醇生物合成的错误到药物毒性和药物毒性和暴露。脂质过氧化经常与神经退行性疾病有关，这项研究与公共卫生的相关性是在过氧化化学和生物学中的基本研究及其在此处提出的与神经退行性疾病的抑制作用的联系，包括毁灭性综合征，SLOS。