Pathogenesis and Treatment of Inherited Cholesterol Deficiency

遗传性胆固醇缺乏症的发病机制和治疗

• 批准号: 7223501
• 负责人: CEDRIC HOWARD SHACKLETON
• 金额: $ 27.05万
• 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/7223501
• 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; Numbers; Object Attachment; Oxidoreductase; Pathogenesis; Patients; Performance; Personal Satisfaction; Phenotype; Positioning Attribute; Preventive; Principal Investigator; Quality of life; Range; Research Personnel; Role; Safety; Sampling; Screening procedure; Serum; Severities; Severity of illness; Siblings; Smith-Lemli-Opitz Syndrome; Staging; Steroids; Sterols; Testing; Thinking; Time; Tissues; Urine; Viral Vector; Week; analog; base; behavior test; brain tissue; day; disease characteristic; enzyme activity; grasp; improved; in utero; in vivo; morris water maze; mouse model; mutant; nervous system disorder; novel diagnostics; prenatal; research study; retinal rods; sex; tool; treatment effect; urinary; vector; young adult

DESCRIPTION (provided by applicant): 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-delta7-reductase (DHCR7). Biochemically, it is characterized by low concentrations of cholesterol (C) in blood and tissues and high concentrations of dehydrocholesterol (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: (Aim 1) 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.

描述（由申请人提供）：Smith-Lemli-Opitz 综合征 (SLOS) 是一种缺乏足够治疗选择的形态畸形和精神发育迟滞障碍。它是由于 7-脱氢胆固醇-δ7-还原酶 (DHCR7) 失活而导致胆固醇缺乏所致。从生化角度看，其特点是血液和组织中胆固醇（C）浓度低，而脱氢胆固醇（DHC）浓度高。尽管 DHCR7 基因的突变已得到很好的描述，但疾病特征的致病发展尚不清楚。在代谢遗传性错误中，SLOS 相对常见，新的诊断方法有助于其产前检测。该提案的长期目标是为 SLOS 的治疗奠定基础。在实验中，将使用高度模仿人类 SLOS 的小鼠模型。提出了三个具体目标：（目标 1）识别并量化 SLOS 的生化标记。使用高度灵敏的质谱方法，将测量突变小鼠和对照小鼠的血清、尿液和组织中的甾醇和类固醇。 DHC/C 和脱氢类固醇/正常类似物的比率将为评估突变严重程度、发育过程中的生化变化以及治疗效果提供标记。由于 SLOS 的主要特征包括神经系统问题，因此需要特别关注神经类固醇。 （目标 2）使成人和新生儿的胆固醇水平正常化。将使用生化标记来评估膳食胆固醇和基因转移的影响。基因转移实验将利用病毒载体将功能性 DHCR7 基因传递给突变小鼠。由于 SLOS 既是一个发育问题，又是一个因胆固醇代谢缺陷而持续存在的问题，因此将在不同的发育阶段对小鼠进行治疗。这将有助于确定发病机制的时间线，并有助于区分不可逆（不可治疗）和可逆（可治疗）SLOS 特征。目标 3. 纠正胎儿发育期间的胆固醇水平。这里的重点是预防性治疗以及确定发育过程中何时发生不可逆转的损害。生化标志物和畸形特征都将受到监测。稍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物的变化相关。治疗的长期后果、安全性和潜在副作用也将受到监测。由于胆固醇具有多种重要作用，尽管 SLOS 的遗传起源相对简单，但它是一种复杂且具有破坏性的疾病。在北美，SLOS 的发生率估计在两万分之一到三万分之一之间，尽管许多病例被认为从未被诊断出来。通过所提出的使用 SLOS 小鼠的实验，我们希望更多地了解疾病发展的时间和生物化学，并为人类的最终治疗奠定基础。