Inborn Errors of Cholesterol Synthesis

胆固醇合成的先天性错误

• 批准号: 7734670
• 负责人: FORBES Dennison PORTER
• 金额: $ 80.08万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734670
• 关键词: 7-dehydrocholesterol; 7-dehydrocholesterol reductase; Autistic Disorder; Baltimore; Basic Science; Behavioral; Belief; Biochemical; Biological; Biological Process; Brain; Caring; Characteristics; Child; Childhood; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Data; Clinical Research; Clinical Sciences; Collaborations; Complement; Congenital Abnormality; Defect; Developmental Process; Dietary Cholesterol; Disease; Dysmorphology; Dysplasia; Enzymes; Face; Fibroblasts; Gastrointestinal tract structure; Genes; Genetic; Genitalia; Genotype; Goals; Growth; Heart; Hereditary Disease; Human; Inborn Genetic Diseases; Institutes; Kidney; Laboratories; Life; Limb structure; Lung; Mental Retardation; Molecular; Morbidity - disease rate; Mus; Mutation; Neurologic; Pathologic Processes; Patients; Phenotype; Physicians; Process; Proteomics; Residual state; Simvastatin; Smith-Lemli-Opitz Syndrome; Supplementation; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Translations; Work; base; bench to bedside; cholesterol biosynthesis; gene cloning; gene therapy; improved; insight; malformation; mortality; mouse model; neurophysiology; postnatal; prenatal; 7-dehydrocholesterol; 7-dehydrocholesterol reductase; Autistic Disorder; Baltimore; Basic Science; Behavioral; Belief; Biochemical; Biological; Biological Process; Brain; Caring; Characteristics; Child; Childhood; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Data; Clinical Research; Clinical Sciences; Collaborations; Complement; Congenital Abnormality; Defect; Developmental Process; Dietary Cholesterol; Disease; Dysmorphology; Dysplasia; Enzymes; Face; Fibroblasts; Gastrointestinal tract structure; Genes; Genetic; Genitalia; Genotype; Goals; Growth; Heart; Hereditary Disease; Human; Inborn Genetic Diseases; Institutes; Kidney; Laboratories; Life; Limb structure; Lung; Mental Retardation; Molecular; Morbidity - disease rate; Mus; Mutation; Neurologic; Pathologic Processes; Patients; Phenotype; Physicians; Process; Proteomics; Residual state; Simvastatin; Smith-Lemli-Opitz Syndrome; Supplementation; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Translations; Work; base; bench to bedside; cholesterol biosynthesis; gene cloning; gene therapy; improved; insight; malformation; mortality; mouse model; neurophysiology; postnatal; prenatal

Our laboratorys focus is the Smith-Lemli-Opitz syndrome (SLOS) and other inborn errors of cholesterol biosynthesis. SLOS is a human autosomal recessive multiple congenital anomaly/mental retardation syndrome characterized by facial dysmorphology, mental retardation with a characteristic behavioral phenotype, growth retardation, and variable structural anomalies of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia and kidneys. SLOS also has a distinct behavioral phenotype which includes self-injurious and autistic features. Biochemically, patients with SLOS have an inborn error of cholesterol biosynthesis; specifically they have a defect in the conversion of 7-dehydrocholesterol to cholesterol. However, we do not know why these children have such a variety of congenital malformations, and neurological problems. We cloned the gene encoding the 7-dehydrocholesterol reductase, and have subsequently identified mutations in this gene in more than fifty patients with Smith-Lemli-Opitz syndrome. Our laboratory continues to identify mutations in SLOS patients, and to determine residual enzymatic function in patient fibroblasts. This information is being used to establish genotype/enzymatic activity/phenotype correlations for this disorder. We have also isolated the mouse gene encoding this enzyme, and have produced a mouse model for this disorder. We are using this mouse model to further our understanding of how the malformations seen in this syndrome develop, and to further our understanding of the neurophysiological basis of the neurological problems associated with this syndrome. A hypomorphic mouse model of SLOS has also been developed. This mouse model is being used to investigate therapeutic interventions including dietary cholesterol supplementation, simvastatin therapy, and gene therapy. Our SLOS mouse models continue to be used to understand the pathophysiological processes that underlie the birth defects and clinical problems found in SLOS. Various biochemical, molecular, and proteomic approaches are being utilized to investigate these issues. These mouse models are being used to test various prenatal and postnatal therapeutic interventions. One of the most intriguing aspects of SLOS is the distinct behavioral phenotype. Most patients with SLOS have autistic features. We are currently working in collaboration with groups from Kennedy Krieger Institute in Baltimore and NHGRI to further analyze this association and to study whether abnormalities of cholesterol metabolism contribute to autism in general. In addition to SLOS, we have developed mouse models of lathosterolosis, desmosterolosis, and HEM dysplasia. These human syndromes all involve defects in cholesterol synthesis. We are using these mouse models to further our understanding of the biological processes which cause the birth defects found in these syndromes. The basic science work done in this laboratory supports and complements the clinical work also being performed by this Section. The combination of basic science and clinical science work in one Section facilitates the rapid translation of findings from the bench to the bedside and vice versa.

我们的实验室重点是Smith-Lemli-Opitz综合征（SLO）和其他先天胆固醇生物合成的错误。 SLO是一种人类常染色体隐性多个先天性异常/心理迟缓综合征，其特征在于面部畸形，精神迟缓，具有特征性的行为表型，生长迟缓和可变的心脏，肺，肺，脑，脑，胃肠道，胃肠道，饮食，生殖器，生殖器，生殖器，生殖器和kidneys和可变的结构性异常。 SLO还具有独特的行为表型，其中包括自杀和自闭症的特征。从生化上，SLOS患者具有天生的胆固醇生物合成误差。具体来说，它们在7-脱氢胆固醇向胆固醇的转化方面存在缺陷。但是，我们不知道为什么这些孩子会出现如此多种先天性畸形和神经系统问题。我们克隆了编码7-脱氢胆固醇还原酶的基因，并随后鉴定了五十多名史密斯 - 莱姆利 - 奥皮茨综合征患者中该基因中的突变。我们的实验室继续鉴定SLOS患者的突变，并确定患者成纤维细胞中的残留酶促功能。该信息用于建立该疾病的基因型/酶促活性/表型相关性。我们还分离了编码这种酶的小鼠基因，并为该疾病产生了小鼠模型。我们正在使用这种小鼠模型来进一步了解该综合征中观察到的畸形是如何发展的，并进一步了解与该综合征相关的神经系统问题的神经生理基础。还已经开发出一种SLO的肌型小鼠模型。该小鼠模型用于研究治疗性干预措施，包括补充饮食胆固醇，辛伐他汀治疗和基因治疗。 我们的SLO小鼠模型继续用于了解SLO中出生缺陷和临床问题的基础的病理生理过程。 正在利用各种生化，分子和蛋白质组学方法来研究这些问题。 这些小鼠模型用于测试各种产前和产后治疗干预措施。 SLO最有趣的方面之一是独特的行为表型。 大多数SLO患者具有自闭症特征。 我们目前正在与巴尔的摩肯尼迪·克里格研究所（Kennedy Krieger Institute）和NHGRI的团体合作，以进一步分析该关联，并研究胆固醇代谢异常是否有助于自闭症。 除SLO外，我们还开发了板塞洛氏菌病，降霉菌病和下摆发育不良的小鼠模型。 这些人类综合征都涉及胆固醇合成中的缺陷。 我们正在使用这些小鼠模型来进一步了解引起这些综合征中出生缺陷的生物学过程。 本节也支持该实验室中的基础科学工作，并补充了本节的临床工作。 基础科学与临床科学工作的结合在一个部分中有助于从长凳上迅速翻译成发现，反之亦然。