权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Elucidating the Role of Sonic Hedgehog Signaling in Cells Along the Astrocyte Lineage

阐明 Sonic Hedgehog 信号在星形胶质细胞谱系细胞中的作用

基本信息

批准号：
10598452
负责人：
Anna Denise Resurreccion Garcia
金额：
$ 40.4万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598452
关键词：
3-Dimensional Ablation Address Astrocytes Bioinformatics Biology Blood - brain barrier anatomy Brain Brain Diseases Cell Lineage Cells Characteristics Compensation Complement Data Development Disease Gene Expression Genetic Transcription Goals Health Ions Maps Mediating Molecular Molecular Genetics Morphogenesis Morphology Neuroglia Neurons Neurotransmitters Oligodendroglia Perinatal Phenotype Play Population Production Property Prosencephalon Regulation Role SHH gene Signal Pathway Signal Transduction Synapses astrocyte progenitor cell type cellular transduction experimental study high resolution imaging injured insight loss of function molecular phenotype neural circuit neural repair neuromechanism new therapeutic target novel postnatal postnatal development progenitor programs reconstruction repaired restoration smoothened signaling pathway stem cells synaptogenesis tool transcriptome sequencing

项目摘要

PROJECT SUMMARY The goal of this proposal is to determine whether molecularly distinct progenitor cells give rise to local astrocyte diversity. Astrocytes are estimated to comprise up to 40% of cells in the brain and growing evidence now shows that these cells possess diverse phenotypic and molecular characteristics. Nevertheless, large gaps remain in our understanding of how such distinct characteristics arise. This study focuses on the role of the molecular signaling pathway, Sonic hedgehog (Shh), which distinguishes a population of perinatal glial progenitor cells in the forebrain. Fate mapping experiments show that these progenitors generate half the population of cortical astrocytes, suggesting that the cortex harbors astrocytes from multiple lineages. The precise role of Shh signaling in astrocyte development is not well understood. This study applies molecular genetic tools together with high resolution imaging and 3D reconstruction of single cells, together with RNASeq and bioinformatic analysis to address the role of Shh signaling in defining lineage-specific phenotypic and molecular characteristics of astrocytes. We will first identify the progenitor cell responsible for Shh-mediated astrocyte production and define unique characteristics of cells within this lineage. We will then apply loss of function strategies together with RNASeq and bioinformatic analysis to interrogate the role of Shh signaling in astrocyte development and molecular identity. Finally, we will use a cellular ablation approach to determine the functional significance of cells derived from the Shh lineage. This study will advance our understanding of astrocyte diversity in the brain and illuminate novel roles for Shh signaling in cell and brain development.

项目概要该提案的目标是确定分子上不同的祖细胞是否会产生局部星形胶质细胞多样性。据估计，星形胶质细胞占大脑细胞的 40%，并且在不断生长现在的证据表明这些细胞具有不同的表型和分子特征。然而，我们对这些独特特征如何产生的理解仍然存在很大差距。这项研究重点关注分子信号传导途径 Sonic Hedgehog (Shh) 的作用，该途径区分了前脑中围产期神经胶质祖细胞群。命运图谱实验表明，这些祖细胞产生了一半的皮质星形胶质细胞，表明皮质中含有星形胶质细胞来自多个血统。 Shh 信号在星形胶质细胞发育中的确切作用尚不清楚。这项研究将分子遗传学工具与高分辨率成像和 3D 重建结合起来单细胞，结合 RNASeq 和生物信息分析来解决 Shh 信号在定义星形胶质细胞的谱系特异性表型和分子特征。我们将首先识别祖细胞负责 Shh 介导的星形胶质细胞的产生并定义细胞的独特特征在这个血统之内。然后我们将应用功能丧失策略以及 RNASeq 和生物信息学分析询问 Shh 信号在星形胶质细胞发育和分子身份中的作用。最后，我们将使用细胞消融方法来确定源自 Shh 的细胞的功能意义血统。这项研究将增进我们对大脑星形胶质细胞多样性的理解，并阐明新的 Shh 信号在细胞和大脑发育中的作用。