Basic and Translational Studies of Inborn Errors of Metabolism

先天性代谢缺陷的基础与转化研究

• 批准号: 10686726
• 负责人: Forbes Porter
• 金额: $ 215.21万
• 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/10686726
• 关键词: 7-dehydrocholesterol; Adolescent; Adult; Affect; Age; Basic Science; Behavioral; Belief; Biochemical Process; Biocompatible Materials; Biological; Biological Models; Blindness; Blood; Brain; CLN3 gene; Cardiac; Cell Line; Cell physiology; Cells; Cerebellar Diseases; Child; Childhood; Cholesterol; Clinical Data; Clinical Protocols; Clinical Research; Clinical Sciences; Collaborations; Collection; Complement; Creatine; Data; Databases; Dementia; Development; Developmental Process; Diagnostic tests; Disease; Dysmorphology; Enrollment; Enzymes; Face; Fibroblasts; Fireflies; Foundations; Functional disorder; Funding; Gastrointestinal tract structure; Genes; Genetic Diseases; Genital; Genitalia; Goals; Growth; Heart; Heart Abnormalities; Hereditary Disease; Human; Impaired cognition; Impairment; Inborn Errors of Metabolism; Incidence; Individual; Infant; Kidney; Laboratories; Laboratory Research; Learning; Limb structure; Link; Lipids; Lobule; Lung; Lysosomal Storage Diseases; Medical Research; Modeling; Molecular; Morbidity - disease rate; Multipotent Stem Cells; Mus; Mutation; NPC1 gene; National Center for Advancing Translational Sciences; Natural History; Neonatal Screening; Neurodegenerative Disorders; Niemann-Pick Diseases; Obsessive compulsive behavior; Participant; Pathologic; Pathologic Processes; Pathology; Patient Care; Patients; Phenotype; Problem behavior; Process; Proteins; Psyche structure; Research; Sampling; Seizures; Smith-Lemli-Opitz Syndrome; Spielmeyer-Vogt Disease; Structural defect; Supraoptic Vertical Ophthalmoplegia; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Translational Research; Work; Zebrafish; autistic; base; behavioral phenotyping; biomarker discovery; biomarker identification; biomarker validation; boys; clinical care; congenital anomaly; creatine transporter; drug testing; heart function; improved; induced pluripotent stem cell; insight; malformation; mortality; mouse model; mutant; pediatric patients; potential biomarker; prognostic value; progressive neurodegeneration; protein biomarkers; rare genetic disorder; transcriptomics; translational study; whole genome

This project supports the basic and translational science research conducted by the Section on Molecular Dysmorphology. This project complements and synergizes with the clinical science conducted under project HD008989. It consolidates and extends work previously done under project HD000139. The rare genetic disorders being studied in the Section on Molecular Dysmorphology (SMD) currently Smith-Lemli-Opitz syndrome, Niemann-Pick disease, type C, CLN3 disease (Batten Disease) and Creatine Transporter Deficiency. The goal of SMD is to use model systems to understand pathological processes contributing to these disorders to identify, develop and test potential biomarkers and therapeutic interventions. These model systems include mouse models, zebrafish models, patient fibroblasts and induced pluripotent stem cells. Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol synthesis with an incidence on the order of 1/50,000. SLOS is an autosomal recessive multiple congenital anomaly/cognitive impairment syndrome characterized by facial dysmorphology, growth retardation and variable structural anomalies of the heart, lungs, brain gastrointestinal tract, genitalia, kidneys, and limbs. Mutations of DHCR7, the gene that encodes an enzyme that converts 7-dehydrocholesterol to cholesterol underly SLOS. Individual with SLOS manifest variable cognitive impairment ranging from mild learning difficulties to profound mental dysfunction. SLOS has a distinct behavior phenotype which includes self-injurious, obsessive compulsive and autistic features. SMD has evaluated over 120 individuals with SLOS in a natural history trial. SMD has developed multiple SLOS mouse models and a zebrafish model of SLOS. We also have produced and studied induced pluripotent stem cells. Niemann-Pick disease type C (NPC) is a lysosomal disease caused by impaired intracellular cholesterol transport. NPC can be caused by mutation of either NPC1 or NPC2, and its incidence is on the order of 1/100,000. This is a lethal neurodegenerative disorder characterized by progressive cerebellar dysfunction and dementia. While most of the patients are children, the participants range in age from infants to adults. SMD has enrolled approximately 140 individuals in our ongoing, longitudinal natural history/observational trial. This clinical protocol provides for deep phenotyping and biomaterial collection. Significant effort has been invested in using the mouse model to identify potential lipid and protein biomarkers that can then be evaluated in human samples. This work has led to development of a blood-based diagnostic test and a newborn screen. Cerebellar lobule specific and cerebellar single cell transcriptomic data from control and mutant NPC1 mice. These databases provide insight into disease pathology and potential therapeutic interventions that can subsequently be tested in the laboratory. In addition to utilizing NPC1 mouse models, SMD has developed and characterized zebrafish models of both NPC1 and NPC2. SMD has also been involved in the development of multiple induced multipotent stem cell lines for the study of NPC1. Whole genome synthetic lethality and cholesterol storage reduction screens have been conducted using these cell lines and this work has given rise to candidate treatments that are being explored. The laboratory has been involved in both biomarker discovery and validation in large sample sets in order to facilitate drug testing and prognostic ability. This work has been supported and facilitated by collaboration with the Ara Parseghian Medical Research Foundation, National Niemann-Pick Disease Foundation, SOAR-NPC and Firefly Fund. CLN3-disease, or juvenile Batten disease, is a recessive lysosomal disease characterized by progressive blindness, seizures, dementia, and behavioral issues. CLN3-disease is due to mutations of CLN3, a gene that encodes a protein of unknown function. SMD has initiated a longitudinal natural history trial which includes deep phenotyping and biomaterial collection for biomarker identification. As part of a NCATS project, SMD is participating in a multicenter natural history trial sponsored by Ultragenyx which is enrolling individuals with Creatine Transported Deficiency (CTD). CTD is an X-linked disorder causing severe cognitive impairment and seizures in affected boys. After identification of cardiac issues in the natural history trial, SMD has been studying a mouse model of CTD to further characterize the abnormal cardiac function.

该项目支持分子畸形学部分进行的基本和转化科学研究。该项目与根据HD008989项目进行的临床科学进行了补充并与之协同。 它合并并扩展了先前根据项目HD000139完成的工作。 目前Smith-Lemli-Opitz综合征，Niemann-Pick病，C型，CLN3疾病（Batten病）和肌酸转运蛋白转运蛋白缺乏症的分子畸形（SMD）部分中所研究的罕见遗传疾病。 SMD的目的是使用模型系统来了解有助于这些疾病的病理过程，以识别，开发和测试潜在的生物标志物和治疗干预措施。 这些模型系统包括小鼠模型，斑马鱼模型，患者成纤维细胞和诱导的多能干细胞。 Smith-Lemli-Opitz综合征（SLO）是胆固醇合成的天生错误，其发病率是1/50,000。 SLOS是一种常染色体隐性多个先天性异常/认知障碍综合征，其特征是面部畸形，生长迟缓和心脏，肺，脑部胃肠道，生殖器，生殖器，肾脏和肢体的可变结构异常。 DHCR7的突变，该酶的基因将7-脱氢胆固醇转化为胆固醇的基因。具有SLOS的个人表现出可变的认知障碍，从轻度学习困难到严重的心理功能障碍。 SLO具有独特的行为表型，其中包括自我伤害，强迫性强迫和自闭症特征。在一项自然历史试验中，SMD评估了120多名SLO的人。 SMD开发了多个SLO小鼠模型和SLO的斑马鱼模型。我们还产生并研究了诱导的多能干细胞。 Niemann-pick疾病C型（NPC）是由细胞内胆固醇转运受损引起的溶酶体疾病。 NPC可能是由NPC1或NPC2的突变引起的，其发病率在1/100,000。这是一种致命的神经退行性疾病，其特征是进行性小脑功能障碍和痴呆症。虽然大多数患者是儿童，但参与者的年龄从婴儿到成人。 SMD已在我们正在进行的纵向自然历史/观察试验中招募了大约140个人。该临床方案提供了深层的表型和生物材料收集。 已经投入了大量精力，用于使用小鼠模型来识别潜在的脂质和蛋白质生物标志物，然后可以在人类样品中评估。这项工作导致了基于血液的诊断测试和新生儿筛查的发展。 小脑小叶特异性和小脑单细胞转录组数据来自对照和突变的NPC1小鼠。 这些数据库提供了有关疾病病理学和潜在治疗干预措施的洞察力，随后可以在实验室中进行测试。 除了利用NPC1小鼠模型外，SMD还开发并表征了NPC1和NPC2的斑马鱼模型。 SMD还参与了多个诱导的多能干细胞系的发展，以研究NPC1。使用这些细胞系进行了整个基因组合成致死性和胆固醇储存筛查，这项工作引起了正在探索的候选治疗。该实验室参与了大型样品集中的生物标志物发现和验证，以促进药物测试和预后能力。 这项工作得到了与ARA Parseghian医学研究基金会，国家Niemann-Pick Disease Foundation，Soar-NPC和Firefly Fund的合作的支持和促进。 CLN3-疾病或青少年骨质疾病是一种隐性溶酶体疾病，其特征是进行性失明，癫痫发作，痴呆症和行为问题。 CLN3-酶酶是由于CLN3的突变引起的，该基因编码了功能未知的蛋白质。 SMD启动了一项纵向自然历史试验，其中包括深层表型和生物材料收集，用于生物标志物鉴定。 作为NCATS项目的一部分，SMD参加了由Ultragenyx赞助的多中心自然历史试验，该试验正在注册患有肌酸运输缺陷（CTD）的人。 CTD是一种X连锁疾病，导致受影响男孩的严重认知障碍和癫痫发作。在自然历史试验中鉴定出心脏问题后，SMD一直在研究CTD的小鼠模型，以进一步表征异常的心脏功能。