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:
- 金额:$ 43.28万
- 依托单位:
- 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:
- 关键词:7-dehydrocholesterol7-dehydrocholesterol reductaseAY9944AffectAlzheimer&aposs DiseaseAntioxidantsAutistic DisorderBiologicalBiological AssayBiologyBrainCell Culture TechniquesCell LineCellsChemistryCholecalciferolCholesterolCholesterol HomeostasisCollectionComplexControl GroupsDefectDesmosterolDevelopmentDiseaseDistributional ActivityDrug ExposureDrug toxicityEnzymesEpoxy CompoundsExhibitsExposure toFibroblastsFollow-Up StudiesFree RadicalsFrequenciesFunctional disorderGene ExpressionGeneticGrantHealthHereditary DiseaseHumanHuman BiologyHuntington DiseaseIndividualInfantIsotopesKnockout MiceLaboratoriesLanosterolLeadLibrariesLightLinkLipid PeroxidationLipid PeroxidesLipidsLiquid substanceMeasurableMeasuresMental RetardationMetabolicMetabolic DiseasesMetabolismMethodsModelingModificationMolecularMutant Strains MiceMutationNerve DegenerationNeurobiologyNeurodegenerative DisordersNeuronal DifferentiationNeuronsNuclear ReceptorsOrganOxidative StressOxygenParkinson DiseasePathologyPathway interactionsPatientsPeroxidesPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhenotypePlasmaPlayProcessProteinsProtocols documentationPublic HealthRattusRecordsResearchRodentRoleSamplingSmith-Lemli-Opitz SyndromeStandard PreparationsSterol Biosynthesis PathwaySterolsSymptomsSyndromeTherapeutic StudiesTissuesTreatment-related toxicityVariantWorkadductbrain abnormalitiescholesterol biosynthesiscongenital anomalyhuman diseasein vivolipid biosynthesismortalitymouse modelneuroblastoma celloxidationperoxidationpostnatalpublic health relevancescreeningsmall 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.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ned Allen Porter其他文献
Ned Allen Porter的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ned Allen Porter', 18)}}的其他基金
FREE RADICALS, MEMBRANES AND ENZYME PHOTOACTIVATION
自由基、膜和酶光活化
- 批准号:
7605523 - 财政年份:2006
- 资助金额:
$ 43.28万 - 项目类别:
FREE RADICALS, MEMBRANES AND ENZYME PHOTOACTIVATION
自由基、膜和酶光活化
- 批准号:
7731348 - 财政年份:2006
- 资助金额:
$ 43.28万 - 项目类别: