Genetic Underpinnings of CM and SM and Effect on Brain Development

CM 和 SM 的遗传基础及其对大脑发育的影响

• 批准号: 10629121
• 负责人: Gabriel E Haller
• 金额: $ 14.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629121
• 关键词: 3-Dimensional; Affect; Animal Model; Bioinformatics; Biological; Brain; Brain Stem; Cerebellar tonsil; Cerebellum; Cerebrospinal Fluid; Cerebrospinal fluid shunts procedure; Childhood; Classification; Clinical; Clinical Treatment; Collaborations; Complex; Craniosynostosis; Cyst; Data; Data Set; Development; Disease; Disparate; Engineering; Etiology; Fishes; Genes; Genetic; Genetic Models; Genetic Variation; Genotype; Goals; Head circumference; Human; Hydrocephalus; Individual; Knock-out; Lead; Liquid substance; Macrocephaly; Magnetic Resonance Imaging; Measurement; Methods; Microsurgery; Modeling; Mutation; NF1 gene; Natural History; Neurologic; Neurologic Symptoms; Neurosurgeon; Obstruction; Operative Surgical Procedures; Outcome; Pathology; Pathway interactions; Patients; Phenotype; Physiology; Positioning Attribute; Predictive Factor; Proteins; Radiology Specialty; Risk; Role; Severities; Skeletal system; Spinal Canal; Spinal Fusion; Spine surgery; Stents; Syringomyelia; System; Testing; Time; Tonsil; Variant; Vertebral column; Zebrafish; accurate diagnosis; body system; brain overgrowth; brain volume; cerebrospinal fluid flow; cohort; comorbidity; cranium; de novo mutation; exome sequencing; foramen magnum; gene discovery; genetic risk factor; genetic variant; genome wide association study; hindbrain; imaging biomarker; insight; malformation; neurosurgery; rare variant; repaired; trait; venous sinus; ventricular system

PROJECT SUMMARY Chiari type I malformation (CM1), the herniation of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions, found in approximately 1 in 1000 individuals. CM1 is characterized by the herniation of the cerebellum through the foramen magnum into the spinal canal, often leading to syringomyelia (SM), a fluid-filled cyst within the spinal canal, obstruction of normal cerebrospinal fluid flow, compression of the brainstem and numerous neurological symptoms. We now have identified some of the first genetic causes of CM1 and have identified idiopathic macrocephaly as a major etiological subtype of CM1. By identifying additional genetic factors underlying CM1 and CM1-related imaging biomarkers, we hope to uncover additional CM1 subtypes and their genetic basis. Additionally, our goal is to understand the role of CM1- associated genetic variation that we have already identified by modeling specific genetic variants in zebrafish to determine what systems are affected (brain, spine, skull, ventricular system) that lead to the common outcome of hindbrain displacement. Earlier and more accurate diagnoses for CM1 patients will have profound effects, informing clinical decisions regarding who should undergo surgery (versus CSF shunting vs surgery+spinal fusion vs observation, etc) and along what time frame.

项目摘要 Chiari I型畸形（CM1），小脑通过孔的疝进入脊柱 运河是最常见的小儿神经系统疾病之一，大约有1000人中有1个。 CM1的特征在于小脑通过孔的大脑催眠到脊柱管中， 通常导致脊髓瘤（SM），脊柱内的液体囊肿，正常脑脊髓的阻塞 流体流动，脑干的压缩和许多神经系统症状。我们现在已经确定了一些 CM1的第一个遗传原因，并将特发性脑畸形确定为主要的病因学亚型 CM1。通过确定CM1和CM1相关成像生物标志物的其他遗传因素，我们希望能够 发现其他CM1亚型及其遗传基础。此外，我们的目标是了解CM1-的作用 我们已经通过对斑马鱼中的特定遗传变异进行建模到已确定的相关遗传变异 确定哪些系统受到影响（大脑，脊柱，头骨，心室系统），导致共同结果 后脑位移。 CM1患者的较早，更准确的诊断将产生深远的影响， 告知有关谁应该接受手术的临床决定（与CSF相对于手术+脊柱 融合与观察等）以及在什么时间范围内。