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CRCNS: Defining the role of astrogenesis in cortical folding

CRCNS：定义星形发生在皮质折叠中的作用

基本信息

批准号：
10831118
负责人：
Maria Holland
金额：
$ 14.43万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-06 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10831118
关键词：
Area Astrocytes Autocrine Communication Behavior Biochemical Biological Brain Calibration Cell Density Cell division Cells Central Nervous System Cerebrum Collaborations Computer Models Coupled Couples Development Developmental Process Diagnostic Disease Electroporation Event Experimental Designs Ferrets Functional disorder Genetic Goals Growth Health Image Infection Investigation Knowledge Measures Mechanics Mission Modeling Molecular Morphology Motion National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurodevelopmental Disorder Neuroglia Neuroimmune Neuronal Plasticity Neurons Neurosciences Oligodendroglia Pathologic Processes Pathway interactions Pattern Physiological Processes Play Population Process Proliferating Public Health Publications Research Role Structure Surface Testing Time Tissues Work biomechanical model cell behavior cell motility cell type computer framework cost data modeling effective therapy experience experimental study in silico in utero in vivo insight mechanical force nervous system disorder novel prenatal response risk prediction spatiotemporal subventricular zone white matter

项目摘要

Glial cells, including astrocytes, are the most prevalent cell type in the brain by far, and their dysfunctions are known to play a role in a host of neurodevelopmental, neurodegenerative, neuroimmune, and neuroplastic diseases and disorders. However, they have been greatly understudied relative to neurons, and it remains unclear what role, if any, they play in cortical folding. Therefore, there is a critical need for deeper mechanistic understanding of the role of glial cells in brain development across health and disease. The long-term goals of the PI and co-I are to use their backgrounds, in computational mechanics and molecular and cellular neuroscience, respectively, to understand the process of cortical folding. Here they combine their complementary expertise to investigate the role of astrocytes in gyrification using a combined computational-experimental approach. The overall objective of this CRCNS proposal is to relate cellular behavior at the microscale to cerebral morphology and cortical folding at the macroscale. In particular, we will evaluate two potential mechanisms of astrocyte proliferation: 1) that astrocytes push on the cortex or 2) that the cortex pulls on astrocytes, causing them to grow in response. To that end, we will experimentally manipulate and track astrocytes in the developing ferret brain using in utero electroporation (Aim 1), develop and calibrate computational models of both mechanisms of astrocyte behavior in cortical folding (Aim 2), and use our models to evaluate their likelihood (Aim 3). This proposal is strongly founded on our own prior work, which has shown that astrocyte proliferation under gyri is necessary for the formation of cortical folds in the ferret brain, and that an experimentally-calibrated computational model can capture the dynamics of cellular behavior and the resulting tissue-level mechanics and morphology. The combined experimental-computational approach proposed here will contribute to our fundamental understanding of the role of glial cells in brain development, which could be important in the study of neurodevelopmental diseases and disorders, advanced diagnostics, and effective treatments. Furthermore, our experimentally-validated computational framework could be used to design experimental approaches to test mechanistic hypotheses and to identify pathways for treatment in spatio- or temporally-specific events such as prenatal infection, illness, or exposure.

胶质细胞，包括星形胶质细胞，是目前为止大脑中最普遍的细胞类型，它们的功能失调