Understanding the mechanisms of congenital hydrocephalus using genomic sequencing approaches

使用基因组测序方法了解先天性脑积水的机制

• 批准号: 10789333
• 负责人: Zechen Chong
• 金额: $ 39.29万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10789333
• 关键词: Abnormal Cell; Acceleration; Affect; Alabama; Biological; Biomedical Research; Brain; Cells; Cerebral Ventricles; Cerebrospinal Fluid; Child; Clinical; Congenital Hydrocephalus; Data; Development; Disease; Etiology; Failure; Family; Genes; Genetic; Genetic Variation; Genomic approach; Genomics; Germ-Line Mutation; Goals; Health; Healthcare Systems; Hemorrhage; Heterogeneity; Human; Hydrocephalus; Individual; Infection; Infrastructure; Knowledge; Life; Link; Live Birth; Methods; Mission; Molecular; Mutation; Neuronal Plasticity; Neurons; Normal tissue morphology; Nucleic Acid Regulatory Sequences; Operative Surgical Procedures; Outcome; Patients; Phenotype; Play; Prevalence; Prevention; Procedures; Public Health; Research; Resources; Role; Sampling; Somatic Mutation; Swab; Technology; Testing; Tissue Sample; Tissues; United States National Institutes of Health; Variant; Ventriculostomy; Work; accurate diagnosis; biobank; brain tissue; cell type; effective intervention; effective therapy; exome sequencing; genome sequencing; genomic tools; improved; innovation; insertion/deletion mutation; insight; multiple omics; novel; personalized intervention; phenomics; single cell analysis; single cell sequencing; tool; whole genome

Congenital Hydrocephalus (CH) is a condition that affects the brain and results from an abnormal accumulation of cerebrospinal fluid (CSF) within the cerebral ventricles. The current treatments for hydrocephalus are surgical interventions, which accompanies a high failure rate. Although extrinsic factors such as hemorrhage or infections may cause CH, recent studies have identified some CH-associated genes or mutations, emphasizing the role of genetics in CH. However, these genetic factors only account for approximately 22% of sporadic CH cases, and many cases remain unsolved. Therefore, there is an urgent need to accelerate the understanding of CH through the cutting-edge technologies. Without leveraging these novel methods, the discovery of additional causal genetic factors of CH and the advancement of accurate diagnoses and treatments may be hindered. The long- term goal is to understand the molecular mechanisms and consequences underlying CH using orthogonal phenomic, genetic, and multi-omics approaches. The overall objective is to develop and apply new genomics tools to advance our understanding of the biological mechanisms of CH. The central hypothesis is that there are additional genetic variations in germline or somatic and/or specific malfunctioning cell types that contribute to the etiology of CH. To test this hypothesis, the PIs and team will pursue the following aims. 1) Comprehensive characterization of all forms of variations in both germline and somatic tissue from CH patients with short- and long- read whole genome sequencing. 2) Identification of abnormal cell types and understanding their function and contribution to CH through single-cell genomics analysis. Upon completion, it is expected that new variations either in the germline or somatic may contribute to CH.

先天性脑积水 (CH) 是一种影响大脑的疾病，是由异常积水引起的 脑室内的脑脊液（CSF）。目前脑积水的治疗方法是手术 干预措施，但失败率很高。尽管出血或感染等外在因素 可能会导致CH，最近的研究已经确定了一些CH相关基因或突变，强调了CH的作用 CH 中的遗传学。然而，这些遗传因素仅占散发性慢性肝炎病例的约 22%，并且 许多案件仍未解决。因此，迫切需要通过以下方式加速对CH的理解： 尖端技术。如果不利用这些新方法，就会发现额外的因果关系 CH的遗传因素以及准确诊断和治疗的进展可能会受到阻碍。长- 术语目标是使用正交法了解 CH 的分子机制和后果 表组学、遗传学和多组学方法。总体目标是开发和应用新的基因组学 增进我们对 CH 生物学机制的理解的工具。中心假设是有 种系或体细胞和/或特定功能障碍细胞类型的额外遗传变异有助于 CH 的病因学。为了检验这一假设，PI 和团队将追求以下目标。 1）综合性 对 CH 患者的种系和体细胞组织中所有形式的变异进行表征 长读长全基因组测序。 2) 识别异常细胞类型并了解其功能 以及通过单细胞基因组学分析对 CH 的贡献。完成后，预计会有新的变化 种系或体细胞都可能导致 CH。