Pathogenesis/Treatment-Inherited Cholesterol Deficiency

遗传性胆固醇缺乏症的发病机制/治疗

• 批准号: 7582306
• 负责人: CEDRIC HOWARD SHACKLETON
• 金额: $ 26.51万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582306
• 关键词: 7-dehydrocholesterol; 7-dehydrocholesterol reductase; Adult; Adverse effects; Affect; Age; Animals; Attention; Behavioral; Biochemical; Biochemical Markers; Biochemistry; Biological Assay; Birth; Blood; Brain; Cerebrospinal Fluid; Characteristics; Cholesterol; Cholesterol Homeostasis; Dehydrocholesterols; Detection; Development; Diagnosis; Diagnostic Procedure; Diet; Dietary Cholesterol; Discipline; Disease; Dysmorphology; Early Diagnosis; Ensure; Fetal Development; Foundations; Frequencies; Gene Transfer; Genes; Genetic; Goals; Hereditary Disease; Human; Inherited; Institutes; Learning; Liver; Longevity; Measurement; Measures; Mediating; Mental Retardation; Metabolic; Metabolism; Methods; Monitor; Mus; Mutant Strains Mice; Mutation; Nature; Neurologic; Newborn Infant; North America; Oxidoreductase; Pathogenesis; Patients; Performance; Phenotype; Positioning Attribute; Preventive; Principal Investigator; Quality of life; Research Personnel; Role; Safety; Sampling; Screening procedure; Serum; Severities; Severity of illness; Siblings; Smith-Lemli-Opitz Syndrome; Staging; Steroids; Sterols; Testing; Time; Tissues; Urine; Viral Vector; analog; base; behavior test; brain tissue; disease characteristic; enzyme activity; grasp; improved; in utero; in vivo; morris water maze; mouse model; mutant; nervous system disorder; neuromuscular; neurosteroids; novel diagnostics; prenatal; research study; retinal rods; sex; tool; treatment effect; urinary; vector; young adult

Smith-Lemli-Opitz syndrome (SLOS) is a dysmorphology and mental retardation disorder lacking adequate therapy options. It is caused by cholesterol deficiency due to inactivity of 7-dehydrocholesterol-A7-reductase (DHCR7). Biochemically, it is characterized by low concentrations of cholesterol (C) in blood and tissues and high concentrations of dehydrbcholesterol (DHC). Although mutations in the DHCR7 gene have been well described, the pathogenic development of the disease characteristics is not well understood. Among inherited errors of metabolism, SLOS is relatively frequent, and new diagnostic methods aid its prenatal detection. The long-term objective of this proposal is to develop a basis for the treatment of SLOS. For experiments, mouse models that closely mimic human SLOS will be used. Three Specific Aims are proposed: (Aim1) Identify and quantify biochemical markers of SLOS. Using highly sensitive mass spectrometric methods, sterols and steroids will be measured in serum, urine and tissues of mutant and control mice. Ratios of DHC/C and dehydro steroids/normal analogs will provide markers for evaluating mutant severity, biochemical changes during development and effects of treatments. Because major characteristics of SLOS include neurological problems, special attention is given to neurosteroids. (Aim 2) Normalize cholesterol levels in adults and newborns. The effects of dietary cholesterol and gene transfer will be evaluated using the biochemical markers. Gene transfer experiments will utilize viral vectors to deliver a functional DHCR7 gene to the mutant mice. Because SLOS is both a developmental problem and a continuing problem perpetuated by deficient cholesterol metabolism, mice will be treated at different developmental stages. This will help establish the time line of pathogenesis and aid distinguishing between irreversible (untreatable) and reversible (treatable) SLOS characteristics. (Aim 3) Correct cholesterol levels during fetal development. Here the emphasis is on preventive treatment and establishing when during development irreversible damage occurs. Both biochemical markers and dysmorphic features will be monitored. Later tests for all three Specific Aims will explore neuromuscular and behavioral performance to see if they are correlated with changes in the biochemical markers. Long-term consequences, safety and potential adverse effects of treatment will also be monitored. Because of the multiple essential roles of cholesterol, SLOS is a complicated and devastating disease in spite of its relatively simple genetic origin. The frequency of SLOS in North America is estimated to be in the range of 1 in 20,000 to 30,000, although many cases are thought to be never diagnosed. Through the proposed experiments using SLOS mice, we hope to learn more about the timing and biochemistry of disease development and to establish a basis for eventual treatment in humans.

Smith-Lemli-Opitz综合征（SLO）是缺乏足够的畸形和智障障碍 治疗选择。它是由胆固醇缺乏症引起的，这是由于7-脱氢胆固醇-A7还原酶的无活跃性引起的 （DHCR7）。从生化上，它的特征是血液和组织中的胆固醇（C）低浓度 高浓度的脱氢胆固醇（DHC）。尽管DHCR7基因中的突变很好 描述的是，疾病特征的致病发育尚不清楚。之中 代谢，SLO的遗传错误相对频繁，新的诊断方法有助于其产前 检测。该提案的长期目标是为治疗SLO的治疗基础。为了 实验，将使用紧密模拟人类SLO的小鼠模型。三个具体目标是 提议：（ AIM1）识别和量化SLO的生化标志物。使用高度敏感的质量 光谱法，固醇和类固醇将在突变体的血清，尿液和组织中测量 控制小鼠。 DHC/C和脱氢类固醇/正常类似物的比率将为评估提供标记 突变的严重程度，在发育过程中的生化变化和治疗作用。因为很大 SLO的特征包括神经系统问题，特别注意神经类固醇。 （目标2） 使成人和新生儿的胆固醇水平正常化。饮食胆固醇和基因转移的影响将 使用生化标记进行评估。基因转移实验将利用病毒载体提供 突变小鼠的功能性DHCR7基因。因为SLO既是一个发展问题，又是 持续的问题因胆固醇代谢不足而存在，将在不同的情况下治疗小鼠 发展阶段。这将有助于建立发病机理的时间线，并有助于区分 不可逆（不可治疗）和可逆（可逆的）SLOS特征。 （目标3）正确胆固醇水平 在胎儿发育期间。在这里，重点是预防治疗和确定 发生不可逆的损害发生。生化标记和畸形功能都将是 受监控。以后对所有三个特定目标的测试将探索神经肌肉和行为表现 看看它们是否与生化标记的变化相关。长期后果，安全性和 治疗的潜在不利影响也将受到监测。因为 尽管胆固醇相对简单，但胆固醇是一种复杂而毁灭性的疾病。 北美SLO的频率估计在20,000至30,000中的1范围内 人们认为许多病例从未被诊断出。通过使用SLOS小鼠提出的实验，我们 希望更多地了解疾病发展的时机和生物化学，并为 最终在人类中进行治疗。