Role of TRIM71 in neural stem cell biology and congenital hydrocephalus

TRIM71 在神经干细胞生物学和先天性脑积水中的作用

• 批准号: 10313612
• 负责人: Duy Phan
• 金额: $ 3.09万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10313612
• 关键词: Academic skills; Affect; Animals; Biological; Biological Process; Biology; Birth; Brain; Brain Diseases; Caenorhabditis elegans; Cell Culture Techniques; Cell physiology; Cells; Cerebral Ventricles; Cerebrospinal Fluid; Cerebrospinal fluid shunts procedure; Childhood; Clinical; Colony-Forming Units Assay; Communicating Hydrocephalus; Complement; Congenital Hydrocephalus; Coupled; Defect; Development; Developmental Brain Malformation; Diagnostic; Educational workshop; Exhibits; Failure; Fluid Balance; Fluids and Secretions; Functional disorder; Future; Genes; Genetic; Goals; Histology; Homologous Gene; Human; Hydrocephalus; Impairment; In Vitro; Intracranial Pressure; Knowledge; Laboratories; Lead; Learning; Live Birth; Magnetic Resonance Imaging; Measurement; Measures; Medicine; MicroRNAs; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Morphogenesis; Mus; Mutant Strains Mice; Mutate; Mutation; Nature; Neonatal; Neuroanatomy; Neurodevelopmental Disorder; Neuroepithelial Cells; Neurosciences; Neurosurgeon; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Phylogeny; Physicians; Physiological; Physiology; Preventive measure; RNA-Binding Proteins; Regulation; Research; Role; Scheme; Scientist; Series; Stem cell pluripotency; Techniques; Testing; Therapeutic; Training; Work; absorption; base; career; cerebrospinal fluid flow; clinical decision-making; de novo mutation; epidermal stem cell; exome sequencing; histological studies; improved; in vitro Assay; insight; mortality; mouse model; multidisciplinary; mutant; mutant mouse model; neocortical; nerve stem cell; nestin protein; neurogenesis; neurogenomics; neuroimaging; novel; novel marker; pre-clinical; precision medicine; prenatal; prognostic; stem cell biology; stem cell differentiation; stem cell population; stem cell proliferation; targeted treatment; transcriptome; ventricular system

PROJECT SUMMARY Congenital hydrocephalus (CH) is the most common developmental malformation of the brain affecting 1/1000 births. CH has been classically attributed to failed cerebrospinal fluid (CSF) homeostasis and therefore treated by surgical CSF diversion, with high morbidity and failure rates. The persistence of post- surgical ventriculomegaly in many patients, often with poor neurodevelopmental outcomes, raises questions about our current paradigms of CH and its treatment. Significant gaps in our understanding of the molecular pathogenesis of CH impede the development of preventive measures, targeted therapies, and improved prognostication. By whole exome sequencing, the Kahle lab has identified heterozygous de novo mutations in the TRIM71/lin-41 as the most common genetic cause of human sporadic CH (Jin et al. 2020, Nature Medicine). TRIM71 encodes an RNA-binding protein first discovered in C. elegans as a heterochronic gene that regulates developmental timing of epidermal stem cells. Despite its remarkable evolutionary conservation across phylogeny and robust expression in prenatal neural stem cells (NSCs), the roles of TRIM71 in mammalian brain development and CH are essentially unknown. In preliminary work, I have shown that mouse lines with the murine homolog of the human TRIM71 CH mutation R608H (Trim71R595H/+) or with conditional NSC-specific Trim71 deletion (Nestin-Trim71fl/fl) both recapitulate the severe neonatal-onset communicating hydrocephalus of human patients harboring TRIM71 mutations. The objective of my proposal is to further characterize these models to increase knowledge of human brain development and CH pathogenesis. I hypothesize TRIM71 mutant ventriculomegaly results not from primary cerebrospinal fluid (CSF) over-accumulation, but rather from impaired neurogenesis related to reduced NSC proliferation and precocious NSC differentiation. Aim 1 will characterize the neuroanatomy and CSF physiology of TRIM71-mutant hydrocephalus using brain magnetic resonance imaging (MRI) and direct measurements of CSF hydrodynamics. Aim 2 will elucidate the cellular mechanisms of TRIM71-mutant hydrocephalus using immunofluorescent studies in Trim71 CH mutant mice complemented by in vitro assays using primary NSC cultures. The demonstration that dysregulated neurogenesis rather than primary CSF over-accumulation underlies some CH cases could have paradigm-changing implications that could lead to improved diagnostic, prognostic, and therapeutic strategies, including the prediction of which CH patients may or may not benefit from neurosurgical CSF shunting. These studies will be conducted as part of our long-term goal to develop precision medicine therapies for CH.

项目总结