Pathogenesis/Treatment-Inherited Cholesterol Deficiency

遗传性胆固醇缺乏症的发病机制/治疗

• 批准号: 7084033
• 负责人: CEDRIC HOWARD SHACKLETON
• 金额: $ 27.86万
• 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/7084033
• 关键词: Smith Lemli Opitz syndrome; autosomal recessive trait; behavior test; biomarker; biotechnology; developmental genetics; developmental nutrition; diet therapy; dietary lipid; disease /disorder model; embryo /fetus therapy; gene delivery system; gene therapy; hypocholesterolemia; laboratory mouse; mental retardation; newborn animals; nonhuman therapy evaluation; pathologic process; psychomotor function; steroid biosynthesis; transfection /expression vector

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（SLO）是缺乏适当治疗选择的畸形和智力低下的障碍。它是由胆固醇缺乏症引起的，这是由于7-脱氢胆固醇 - 二甲醇还原酶（DHCR7）的无效。从生化上讲，它的特征是血液和组织中的胆固醇（C）低浓度以及高浓度的脱氢胆固醇（DHC）。尽管已经很好地描述了DHCR7基因中的突变，但疾病特征的致病发育尚不清楚。在代谢的遗传错误中，SLO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。对于实验，将使用紧密模拟人类SLO的小鼠模型。提出了三个具体目标：（目标1）识别和量化SLO的生化标记。使用高灵敏的质谱法，将在突变体和对照小鼠的血清，尿液和组织中测量固醇和类固醇。 DHC/C和脱氢类固醇/正常类似物的比率将为评估突变体严重程度，发育过程中的生化变化和治疗作用提供标记。由于SLO的主要特征包括神经系统问题，因此特别注意神经类固醇。 （AIM 2）将成人和新生儿的胆固醇水平归一化。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将功能性DHCR7基因传递给突变小鼠。由于SLO既是一个发育问题，又是由于胆固醇代谢不足而延续的持续问题，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。在胎儿发育过程中正确胆固醇水平。在这里，重点是预防治疗和确定在发育中发生不可逆损害时。将监测生化标记和畸形特征。以后对所有三个特定目标的测试将探索神经肌肉和行为性能，以查看它们是否与生化标记的变化相关。还将监测长期后果，安全性和潜在的治疗不利影响。由于胆固醇的多重作用，尽管其相对简单的遗传起源，但SLO是一种复杂而毁灭性的疾病。据估计，北美SLO的频率在20,000至30,000中的范围为1个，尽管许多病例被认为从未被诊断出。通过使用SLO小鼠的拟议实验，我们希望更多地了解有关疾病发展的时间和生物化学的更多信息，并为人类最终治疗的基础建立基础。