Clinical and Molecular Studies of Malformations

畸形的临床和分子研究

• 批准号: 8565547
• 负责人: Leslie Biesecker
• 金额: $ 274.32万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 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/8565547
• 关键词: Animal Model; Atrial Heart Septal Defects; Bardet-Biedl Syndrome; Cells; Cleft Palate; Clinical; Clinical Research Protocols; Congenital Abnormality; Development; Diagnostic radiologic examination; Disease; Dysmorphology; Dysplasia; Electroencephalography; Elements; Etiology; Genital system; Hereditary Disease; Human; Human Genetics; Image; Journals; Laboratories; Lenz syndrome 2; Limb structure; Microphthalmos; Molecular; Molecular Biology; Molecular Genetics; Morphology; Mus; Natural History; Operative Surgical Procedures; Other Genetics; PIK3CA gene; Pathogenesis; Physical Examination; Polydactyly; Proteins; Proteus Syndrome; Pulmonary function tests; Recording of previous events; Reporting; Severities; Superior vena cava structure; Syndrome; Techniques; Therapeutic Studies; Translational Research; Ultrasonography; Work; Zebrafish; malformation; methylmalonic aciduria; positional cloning; programs; research clinical testing; tissue/cell culture; tomography; tool; working group

The laboratory uses a translational research approach to study human malformations. In the clinical arena, we operate several clinical research protocols to assess the range of severity, spectrum of malformations, and natural history of pleiotropic developmental anomalies. We use clinical evaluations that include history and physical examination, imaging studies including radiography, ultrasound, and tomography, as well as EEG, pulmonary function testing, etc. to characterize functional and structural anomalies. In selected cases we also perform surgical treatments if they offer clinical benefit and can advance our understanding of the disease under study. Some of the disorders that we are currently studying include non-syndromic polydactyly, Proteus syndrome, non-Proteus asymmetric overgrowth syndrome, Bardet-Biedl syndrome, PIGA-related CNS dysplasia, Ogden syndrome, and Lenz microphthalmia syndrome. We use the tools of modern molecular biology to determine the molecular pathogenesis of these disorders. These include high throughput sequencing, positional cloning, microarray expression and microarray CGH analysis, cell and tissue culture studies to assess cell biologic functions and abnormalities of gene products, and the creation and analysis of animal models of human genetic disease (mouse and zebrafish). Using these techniques in the past year we have elucidated the etiology of PIGA-related CNS dysplasia, TARP syndrome (Talipes, Atrial septal defect, Right superior vena cava, and cleft Palate), Pallister-Hall, McKusick-Kaufman, two forms of Lenz microphthalmia, Oculofaciocardiodental syndromes, combined malonic and methylmalonic acidemia, Proteus syndrome, and PIK3CA-related non-Proteus overgrowth. In addition, Dr. Biesecker is a co-founder and co-director of the Elements of Morphology dysmorphology standards working group. This group is working to standardize malformation descriptions to increase the utility of clinical descriptions and journal reports. The group is currently working on definitions for genital anomalies and an expanded set of limb morphology terms.

该实验室采用转化研究方法来研究人类畸形。在临床领域，我们实施多种临床研究方案来评估严重程度、畸形范围和多效性发育异常的自然史。我们使用包括病史和体格检查在内的临床评估，包括放射线照相、超声和断层扫描在内的影像学研究，以及脑电图、肺功能测试等来表征功能和结构异常。在选定的病例中，如果手术治疗具有临床益处并且可以增进我们对所研究疾病的了解，我们也会进行手术治疗。我们目前正在研究的一些疾病包括非综合征性多指畸形、变形杆菌综合征、非变形杆菌不对称过度生长综合征、Bardet-Biedl 综合征、PIGA 相关中枢神经系统发育不良、奥格登综合征和 Lenz 小眼综合征。 我们使用现代分子生物学工具来确定这些疾病的分子发病机制。其中包括高通量测序、定位克隆、微阵列表达和微阵列 CGH 分析、评估细胞生物学功能和基因产物异常的细胞和组织培养研究，以及人类遗传疾病动物模型（小鼠和斑马鱼）的创建和分析。 在过去的一年中，我们利用这些技术阐明了 PIGA 相关中枢神经系统发育不良、TARP 综合征（Talipes、房间隔缺损、右上腔静脉和腭裂）、Pallister-Hall、McKusick-Kaufman、两种形式的 Lenz 小眼症、眼面心齿综合征、丙二酸和丙二酸相结合的病因。 甲基丙二酸血症、变形杆菌综合征和 PIK3CA 相关的非变形杆菌过度生长。 此外，Biesecker 博士还是 Elements of Morphology 畸形学标准工作组的联合创始人兼联合主任。该小组正在努力标准化畸形描述，以提高临床描述和期刊报告的实用性。该小组目前正在研究生殖器异常的定义和一组扩展的肢体形态术语。