The Novel Role of Cilia in Astrocyte Sevelopment

纤毛在星形胶质细胞发育中的新作用

基本信息

批准号：
10605618
负责人：
Rachel Marie Bear
金额：
$ 4.68万
依托单位：
EMORY UNIVERSITY
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：
2023-03-13 至 2026-01-12
项目状态：
未结题

项目摘要

PROJECT SUMMARY Astrocytes are the most abundant glial cell in the brain and are essential for neural circuit formation and neuron function. Astrocytes have an indispensable role in the developing brain, yet our fundamental understanding of how astrocytes develop trails our knowledge of neuron development. To develop, astrocytes must proliferate at the proper time, genetically differentiate, and morphologically mature. Astrocyte dysfunction contributes to the pathology of several neurodevelopmental disorders, yet these mechanisms are poorly understood. Both neurons and astrocytes possess a primary cilium, a slender microtubule projection, that serves as a specialized signaling center for the cell. Cilia are critical regulators of neuron development. However, despite astrocytes having a primary cilium, the function of astrocyte cilia remains unknown. Disruptions to cilia result in a class of disorders termed ciliopathies that often result in a spectrum of neurological abnormalities. We must establish a fundamental understanding of astrocyte cilia because it is likely that they contribute to such neurodevelopmental diseases. The goal of my research is to create foundational knowledge of the roles that cilia play in astrocyte development. My preliminary data indicate that astrocyte cilia are necessary for several stages of astrocyte development. Loss of astrocyte cilia results in altered proliferation, abnormal cellular morphology, and disrupted expression of developmental astrocyte genes. Therefore, I hypothesize that astrocyte cilia are critical to regulate astrocyte proliferation and differentiation. This project aims to 1) determine how cilia regulate astrocyte proliferation and 2) define the role of cilia in astrocyte differentiation. I will use mouse models to genetically ablate cilia at distinct timepoints, specifically in astrocytes, to investigate the requirements of cilia at different stages of astrocyte development. I will determine whether cilia regulate the timing and rate of astrocyte proliferation. Then, to further define how cilia regulate proliferation, I will monitor cell cycle progression. Next, I will define whether cilia are required for astrocyte differentiation by conducting a morphological analysis of astrocyte size, spacing, and branching features. Finally, I will conduct a transcriptomics analysis to determine whether cilia regulate the genetic program of developing astrocytes. I will also examine astrocyte transcriptional expression at the cellular level to define whether cilia impact differentiation in specific populations of cortical astrocytes. The proposed experiments will reveal novel functions of astrocyte cilia and establish a foundation for the roles of ciliary signaling in astrocyte development. This work will increase fundamental knowledge about astrocyte cilia and how astrocytes develop to improve our understanding of astrocyte contribution to neurodevelopmental diseases.

项目概要星形胶质细胞是大脑中最丰富的神经胶质细胞，对于神经回路的形成和神经元至关重要功能。星形胶质细胞在大脑发育中起着不可或缺的作用，但我们对星形胶质细胞的基本理解星形胶质细胞的发育过程遵循了我们对神经元发育的了解。为了发育，星形胶质细胞必须在适当的时间，遗传分化，形态成熟。星形胶质细胞功能障碍导致一些神经发育障碍的病理学，但人们对这些机制知之甚少。两个都神经元和星形胶质细胞拥有初级纤毛，一种细长的微管突起，充当细胞的专门信号中心。纤毛是神经元发育的关键调节因子。然而，尽管星形胶质细胞具有初级纤毛，但星形胶质细胞纤毛的功能仍然未知。纤毛破坏导致一类称为纤毛病的疾病，通常会导致一系列神经系统异常。我们必须建立对星形胶质细胞纤毛的基本了解，因为它们可能有助于这种作用神经发育疾病。我的研究目标是建立有关以下角色的基础知识：纤毛在星形胶质细胞的发育中发挥作用。我的初步数据表明星形胶质细胞纤毛对于多种功能是必需的星形胶质细胞发育阶段。星形胶质细胞纤毛的丧失导致增殖改变、细胞异常形态，以及发育星形胶质细胞基因表达的破坏。因此，我假设星形胶质细胞纤毛对于调节星形胶质细胞增殖和分化至关重要。该项目的目的是 1) 确定纤毛如何调节星形胶质细胞增殖，2) 定义纤毛在星形胶质细胞分化中的作用。我会用小鼠模型在不同时间点（特别是星形胶质细胞）基因消融纤毛，以研究星形胶质细胞发育不同阶段纤毛的需求。我将确定纤毛是否调节星形胶质细胞增殖的时间和速率。然后，为了进一步确定纤毛如何调节增殖，我将监测细胞周期进展。接下来，我将通过进行星形胶质细胞分化是否需要纤毛来确定星形胶质细胞大小、间距和分支特征的形态学分析。最后，我将进行一次转录组学分析以确定纤毛是否调节星形胶质细胞发育的遗传程序。我会还检查细胞水平的星形胶质细胞转录表达，以确定纤毛是否影响皮质星形胶质细胞特定群体的分化。拟议的实验将揭示新颖的星形胶质细胞纤毛的功能，并为纤毛信号在星形胶质细胞发育中的作用奠定基础。这项工作将增加关于星形胶质细胞纤毛以及星形胶质细胞如何发育以改善的基础知识我们对星形胶质细胞对神经发育疾病的贡献的理解。