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）：我们提出一项关于胆固醇代谢和胆固醇缺乏对 Smith-Lemli-Opitz 综合征 (SLOS) 的影响的研究。 SLOS 是一种胆固醇合成障碍，由编码 7-脱氢胆固醇 (7DHC) 还原酶的 DHCR7 基因突变引起，7-脱氢胆固醇还原酶是胆固醇合成途径中的最终酶。受影响的个体表现出多种畸形和智力低下。 SLOS 的特征被认为主要与胆固醇缺乏和 7DHC 积累有关。然而，临床表型尚未得到很好的表征，生化发病机制尚未完全了解，而且还没有针对这种破坏性疾病的有效治疗方法。因此，我们的首要目标是使用自然历史研究设计更好地定义 SLOS 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、脑髓鞘形成和胆固醇周转受损以及视网膜功能障碍。为了检验这一假设，我们将使用最先进的方法与临床观察、测试和成像并行评估胆固醇稳态。这项自然史子研究将有助于创建全面的 SLOS 自然史登记册并制定临床试验终点。我们的第二个目标是测试辛伐他汀作为补充治疗策略对补充胆固醇的患者的疗效。我们假设 SLOS 患者会对辛伐他汀治疗产生良好反应，通过改善大脑胆固醇合成和增加全身胆固醇池大小。为了验证这一假设，我们将用辛伐他汀治疗补充胆固醇的 SLOS 患者 2 年。与仅接受胆固醇补充剂的患者相比，治疗效果将主要根据认知和行为（临床）的变化来判断，但也会根据替代生化和其他指标（即甾醇和氧甾醇、ERG 和脑 MRI）来判断。这项干预研究将测试 SLOS 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，并为未来的多中心临床试验奠定基础。在这个项目中，我们计划继续将体外研究从实验室转化为临床。我们的第三个目标是阐明 SLOS 发病机制，探讨 DCHR7 缺陷对细胞功能的影响，并评估具有体外治疗潜力的化合物的细胞益处。我们假设 DCHR7 缺陷导致代谢转移远离胆固醇合成，改变质膜小窝的结构、组成和信号功能，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选择性地恢复 SLOS 细胞的代谢和功能。后面的这些研究将在体外使用 SLOS 进行，并对照皮肤成纤维细胞、SLOS 小鼠脑源性细胞和 SLOS 人脑组织。总之，所提出的体内和体外研究应该能够阐明 SLOS 的发病机制，并提供迄今为止研究人员尚未了解的治疗方法。公共健康相关性：该研究项目试图尽可能多地了解史密斯-莱姆利-奥皮茨综合征 (SLOS) 病症，以便开发治疗方法。 SLOS 是胆固醇生成的缺陷；受影响的患者有智力障碍和出生缺陷。与大多数胆固醇过多的胆固醇疾病不同，SLOS 的特点是胆固醇缺乏。研究这种罕见疾病应该可以深入了解胆固醇代谢的总体情况，这对于解决更常见的胆固醇相关问题应该是有用的。