医学创新论坛第82期

时间：2025年9月17日（周三）下午16:00

地点：首都医科大学基础科研楼北楼二层多功能厅

主持人：

柴国梁

首都医学科学创新中心

报告人：

Joseph G. Gleeson

Professor

University of California, San Diego

报告题目：

Genetic Basis of Pediatric Brain Disease: From Molecular Cause to Cell Lineage

摘要：

The developmental origins and lineage relationships of human CNS cells remain poorly understood. Neural cells often arise far from their final destinations, following complex, evolutionarily constrained migration routes.  While vertebrate models provide critical insight, they tend to fall short modeling of neuropsychiatric and other conditions like focal cortical dysplasia and neural tube defects. Differences between mouse and human are emerging that could help explain vulnerabilities, especially for certain cell populations implicated in disease risk. By studying patients with rare CNS diseases, we identified mutated genes and modeled these in mouse, to reveal disrupted cellular pathways.  To understand human-specific roles, we leveraged somatic mosaic variants (MVs) as natural barcodes to map neurogenesis in the human brain. MVs can occur from embryogenesis through adulthood, and are faithfully inherited by daughter cells.  While some MVs lead to disease, the vast majority are benign, where they can serve as inert lineage barcodes.  We developed methodology to interrogate MVs in healthy humans to reveal patterns of neurogenesis that are surprisingly distinct in ways from prior vertebrate model data.  (1) Telencephalic cells are lineage-restricted at the midline before anterior–posterior restriction. (2) A subset of interneurons derives from dorsal neocortical progenitors. (3) Neural crest clones migrate rostrocaudally within the neural tube, later segregating into either sensory or sympathetic ganglia. These lineage patterns have implications for human-specific vulnerabilities to neurodevelopmental and neuropsychiatric disorders.

报告人简介：

Dr. Gleeson trained clinically in child neurology and genetics at the University of Chicago and Boston Children’s Hospital.  He directs the Laboratory for Pediatric Brain Disease at the University of California, San Diego, and Rady Children’s Institute for Genomic Medicine. His research is focused on genetic brain diseases, with the goal of discovering causes, uncovering mechanisms, and developing new treatments.  Projects include: 1] Genetic mosaicism in the developing brain. 2] Patient-derived brain organoids to model disease. 3] Gene-environment interactions as a cause for neural tube defects. 4] Novel therapeutics in treating brain disease including antisense oligonucleotides. He is an Investigator with the Simons Foundation for Autism Research, Chief Medical Officer of the n-Lorem Foundation, and a member of the US National Academy of Science Institute of Medicine. 

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