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

• 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
• 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

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.

神经胶质细胞，包括星形胶质细胞，是目前大脑中最常见的细胞类型，它们的功能障碍 已知在许多神经发育、神经变性、神经免疫和 神经可塑性疾病和紊乱。然而，相对于神经元， 目前还不清楚它们在皮质折叠中起什么作用。因此，迫切需要 更深入地了解神经胶质细胞在健康和疾病中大脑发育中的作用。 PI和co-I的长期目标是利用他们的背景，在计算力学和 分子和细胞神经科学，分别了解皮层折叠的过程。这里他们 联合收割机，他们互补的专业知识，研究星形胶质细胞在脑回化的作用，使用 计算-实验相结合的方法。本CRCNS提案的总体目标是 从微观的细胞行为到宏观的大脑形态和皮质折叠。 特别是，我们将评估星形胶质细胞增殖的两种潜在机制：1）星形胶质细胞推动 或者2）皮质拉动星形胶质细胞，导致它们响应生长。为此我们 将在子宫内实验性地操纵和跟踪正在发育的雪貂大脑中的星形胶质细胞， 电穿孔（目标1），开发和校准星形胶质细胞的两种机制的计算模型 行为在皮质折叠（目标2），并使用我们的模型来评估其可能性（目标3）。这项建议 是建立在我们自己先前的工作基础上的，我们先前的工作表明，脑回下的星形胶质细胞增殖是 雪貂大脑皮层褶皱形成所必需的，实验校准的 计算模型可以捕获细胞行为的动力学和由此产生的组织水平 力学和形态学。本文提出的实验-计算相结合的方法将 有助于我们对神经胶质细胞在大脑发育中的作用的基本理解，这可能是 重要的神经发育疾病和障碍的研究，先进的诊断，和有效的 治疗。此外，我们的实验验证的计算框架可用于设计 实验方法，以测试机制假设，并确定在空间或时间特定的事件，如产前感染，疾病或暴露的治疗途径。