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.

项目概要 Chiari I 型畸形 (CM1)，小脑通过枕骨大孔疝入脊柱 运河，是最常见的儿科神经系统疾病之一，大约千分之一的人中发现。 CM1的特点是小脑通过枕骨大孔突出进入椎管， 通常会导致脊髓空洞症 (SM)，这是一种椎管内充满液体的囊肿，会阻塞正常的脑脊髓 液体流动、脑干受压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，并已将特发性大头畸形确定为 CM1 的主要病因亚型 CM1。通过识别 CM1 和 CM1 相关成像生物标志物背后的其他遗传因素，我们希望 揭示其他 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的特定遗传变异进行建模来识别相关的遗传变异 确定哪些系统受到影响（大脑、脊柱、颅骨、心室系统），从而导致共同结果 后脑移位。对 CM1 患者进行更早、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策（相对于脑脊液分流术与手术+脊柱 融合与观察等）以及沿着什么时间范围。