Dietary Cholesterol and Defects in Cholesterol Synthesis

膳食胆固醇和胆固醇合成缺陷

基本信息

批准号：
7728895
负责人：
Robert David Steiner
金额：
$ 51.33万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-20 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7728895
关键词：
7-dehydrocholesterol 7-dehydrocholesterol reductase Acetylcysteine Acids Adherence Affect Antioxidants Apoptosis Arts Ascorbic Acid Astrocytes Autistic Disorder Behavior Behavioral Bile Acids Biochemical Brain Caveolae Cell membrane Cell physiology Cells Cholesterol Cholesterol Homeostasis Clinical Clinical Research Clinical Treatment Clinical Trials Cognition Congenital Abnormality Defect Development Diet Dietary Cholesterol Disease Dolichol Electrophysiology (science)Enzymes Evaluation Exhibits Exposure to Fibroblasts Foundations Functional disorder Future Genes Goals Hearing Homeostasis Human Hydrogen Peroxide Hydroxycholesterols Image In Vitro Individual Infusion procedures Intake Intervention Intervention Studies Investigation Lead Learning Light Lipids Low-Density Lipoproteins Magnetic Resonance Imaging Measurable Measures Mental Retardation Messenger RNA Metabolic Metabolism Methods Mevalonic Acid Miglustat Molecular Molecular Chaperones Monitor Mus Mutation Natural History Neurocognitive Neurocognitive Deficit Neurons Outcome Oxidative Stress Oxidoreductase Pathogenesis Pathway interactions Patients Phenotype Physiological Physiology Plasma Production Proteins Randomized Rare Diseases Reactive Oxygen Species Registries Research Research Design Research Personnel Research Project Grants Retinal Sensory Shunt Device Signal Transduction Simvastatin Skin Smith-Lemli-Opitz Syndrome Sterols Structure Supplementation Syndrome System Testing Therapeutic Tocopherols Translations Treatment Efficacy Treatment Protocols Triethylenetetramine Ubiquinone Urinary Diversion Variant Vision Wild Type Mouse X ray diffraction analysis X-Ray Diffraction absorption behavior test bench to bedside brain tissue cholesterol absorption clinical phenotype effective therapy efficacy testing fighting improved in vivo indexing inhibitor/antagonist insight intervention effect isoprenoid mRNA Expression malformation myelination protein expression protein folding public health relevance response stable isotope tauroursodeoxycholic acid treatment trial

项目摘要

DESCRIPTION (provided by applicant): We propose a study of cholesterol metabolism and the effects of cholesterol deficiency in Smith-Lemli-Opitz Syndrome (SLOS). SLOS is a disorder of cholesterol synthesis caused by mutations in the DHCR7 gene encoding 7-dehydrocholesterol (7DHC) reductase, the final enzyme in the cholesterol synthetic pathway. Affected individuals exhibit multiple malformations and mental retardation. The features of SLOS are thought to be primarily related to cholesterol deficiency and accumulation of 7DHC. However, the clinical phenotype is not well characterized, the biochemical pathogenesis is incompletely understood, and there is no proven therapy for this devastating condition. Thus our first objective is to better define the phenotype of SLOS using a natural history study design. We hypothesize that impaired cholesterol homeostasis leads to measurable behavioral and neurocognitive deficits, impaired brain myelination and cholesterol turnover, and retinal dysfunction. To test this hypothesis we will assess cholesterol homeostasis using state-of-the-art methods in parallel with clinical observation, testing, and imaging. This natural history sub-study will contribute to creating a comprehensive SLOS natural history registry and to the development of end-points for clinical trials. Our second objective is to test the efficacy of simvastatin as a complementary therapeutic strategy in patients supplemented with cholesterol. We hypothesize that SLOS patients will respond favorably to simvastatin treatment by improving brain cholesterol synthesis and increasing whole body cholesterol pool size. To test this hypothesis, we will treat SLOS patients supplemented with cholesterol for 2 years with simvastatin. Treatment efficacy will be judged primarily on changes in cognition and behavior (clinical) but also on surrogate biochemical and other measures (i.e. sterols and oxysterols, ERG, and brain MRI), in comparison with patients receiving only cholesterol supplementation. This intervention study will test the feasibility of clinical treatment trials in SLOS and the likelihood of efficacy of a promising intervention, as well as provide a foundation for future multicenter clinical trials. In this project, we plan to proceed with translation of in vitro studies from bench to bedside. Our third objective is to elucidate SLOS pathogenesis, probe the consequences of DCHR7 deficiency on cell functions and evaluate the cellular benefit of compounds with therapeutic potential in vitro. We hypothesize that DCHR7 deficiency causes metabolic diversion away from cholesterol synthesis, alters the structure, composition and signaling function of plasma membrane caveolae, impairs ER-specific protein folding activity, and causes cellular oxidative stress and apoptosis. We further hypothesize that statins, bile acids, antioxidants and molecular chaperones selectively restore SLOS cell metabolism and function. These latter studies will be conducted in vitro using SLOS and control skin fibroblasts, SLOS mouse brain-derived cells, and SLOS human brain tissues. Together, the in vivo and in vitro studies proposed should shed light on the pathogenesis of SLOS, and offer insights into treatment that to date have eluded investigators. PUBLIC HEALTH RELEVANCE: This research project represents an attempt to learn as much as we can about a condition called Smith-Lemli- Opitz syndrome (SLOS) in order to develop treatment. SLOS is a defect in cholesterol production; affected patients have mental retardation and birth defects. Unlike most cholesterol diseases which have excess cholesterol, SLOS is characterized by cholesterol deficiency. Studying this rare disease should yield insights into cholesterol metabolism in general, which should prove useful in fighting more common cholesterol related problems.

描述（由申请人提供）：我们提出了一项研究胆固醇代谢以及胆固醇缺乏症对史密斯 - 莱姆利 - 奥皮茨综合征（SLOS）的影响。 SLO是由编码7-脱氢胆固醇（7DHC）还原酶的DHCR7基因突变引起的胆固醇合成的疾病，这是胆固醇合成途径的最终酶。受影响的个体表现出多种畸形和智力障碍。 SLO的特征被认为主要与7DHC的胆固醇缺乏和积累有关。然而，临床表型的表征没有很好地表征，生化发病机理尚未完全理解，并且对于这种毁灭性的疾病没有可靠的治疗。因此，我们的第一个目标是通过自然历史研究设计更好地定义SLO的表型。我们假设胆固醇稳态受损会导致可测量的行为和神经认知缺陷，脑部髓鞘损害和胆固醇更换以及视网膜功能障碍。为了检验该假设，我们将使用与临床观察，测试和成像并行的最先进方法评估胆固醇稳态。这种自然历史子研究将有助于创建全面的SLOS自然历史注册表和临床试验终点的发展。我们的第二个目标是测试辛伐他汀作为补充胆固醇的患者的互补治疗策略的功效。我们假设SLOS患者将通过改善脑胆固醇合成并增加全身胆固醇池的大小来对辛伐他汀治疗做出好评。为了检验该假设，我们将用辛伐他汀治疗补充胆固醇的SLOS患者。与仅接受胆固醇补充剂的患者相比，治疗疗效将主要根据认知和行为的变化（临床）判断（临床）（临床）（临床）（临床）（即替代生化和其他措施（即固醇和氧甲醇，ERG和脑MRI））。这项干预研究将测试SLO中临床治疗试验的可行性以及有希望的干预措施有效性的可能性，并为将来的多中心临床试验提供了基础。在这个项目中，我们计划继续将体外研究从长凳上翻译为床边。我们的第三个目标是阐明SLOS发病机理，探测DCHR7缺乏症对细胞功能的后果，并评估具有治疗潜力的化合物的细胞益处。我们假设DCHR7缺乏会导致代谢转移从胆固醇合成，改变质膜洞穴的结构，组成和信号传导功能，损害ER特异性蛋白质折叠活性，并导致细胞氧化应激和细胞凋亡。我们进一步假设他汀类药物，胆汁酸，抗氧化剂和分子伴侣有选择地恢复SLOS细胞代谢和功能。这些后一种研究将在体外使用SLO和对照皮肤成纤维细胞，SLOS小鼠脑源性细胞和SLOS人脑组织进行体外进行。同时提出的体内和体外研究应阐明SLO的发病机理，并提供有关迄今为止已经避开研究人员的治疗的见解。公共卫生相关性：该研究项目代表了一种尝试尽可能多地了解一种称为史密斯 - 莱姆利兹综合症（SLO）的疾病，以开发治疗。 SLO是胆固醇产生的缺陷；受影响的患者患有智力低下和出生缺陷。与大多数胆固醇过多的胆固醇疾病不同，SLO的特征是胆固醇缺乏症。研究这种罕见疾病应该对胆固醇代谢有所了解，这应该被证明可用于抵抗更常见的胆固醇问题。