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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.