Investigating Functional Ependymal Cell Heterogeneity in the Ventricular System

研究心室系统功能性室管膜细胞异质性

• 批准号: 10456529
• 负责人: Stephanie Redmond
• 金额: $ 5.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456529
• 关键词: Adult; Astrocytes; Automobile Driving; Award; Brain; Cell Transplantation; Cells; Cerebrospinal Fluid; Complex; Data; Dorsal; Embryonic Development; Ependymal Cell; Feeding behaviors; Foundations; Gene Expression Profile; Genes; Heterogeneity; Heterotopic Transplantation; Instruction; Knowledge; Lateral; Life; Molecular; Molecular Genetics; Mus; Nature; Neuraxis; Neuroglia; Neurons; Phase; Positioning Attribute; Radial; Role; Signal Transduction; Stratum Granulosum; Structure; Surface; Testing; Ventricular; Work; adult neurogenesis; brain repair; insight; interest; lateral line; lateral ventricle; mouse genetics; nerve stem cell; neurogenesis; olfactory bulb; relating to nervous system; response; single cell sequencing; single-cell RNA sequencing; stem cell niche; stem cell therapy; tool; two-dimensional; ventricular system

Project Summary/Abstract: The brain is made up of highly specialized neurons and glia, organized spatially into distinct functional units, interconnected to perform some of the most complex computations in nature. To date, cutting-edge molecular and genetic tools have been applied overwhelmingly to the study of neural structure and function. Less well understood are glial cells, despite the fact that radial glia generate all neurons in the central nervous system during embryonic development. Adult neural stem cells (aNSCs) share many features of radial glia and astrocytes, and in mice give rise to new neurons throughout life. aNSCs are present in the lateral walls of the lateral ventricles, and sit in complex cellular niches that regulate many features of their activity. We and others have previously found that the neurogenic potential of aNSCs depends on the aNSC’s position along the two- dimensional surface of the ventricular wall. Dorsal aNSCs generate superficial-layer granular cells for the olfactory bulb, while ventral aNSCs produce deep-layer granular cells. Adult NSC neurogenic potential is cell- intrinsic, as heterotopically transplanted cells produce neurons consistent with their original position. However, instructive niche cell signaling may also be regionally defined, as recent work demonstrates spatially selective aNSC activation directly or indirectly by projection neurons in response to feeding behavior. Given the widespread interest in stem cell therapies for brain repair, a critical gap in knowledge is the lack of mechanistic insight into molecular determinants of aNSC neurogenic potential and of neurogenic niche regionalization. I hypothesize that regionally-restricted transcriptional signatures define aNSC neurogenic potential, and complementary signatures in niche glia underlie region-specific extrinsic control of adult neurogenesis. In this proposal, I put forward three orthogonal Aims that span the K99 and R00 phases of the award. In the first two Aims completed largely in the K99 phase, I use single cell sequencing to identify dorsal and ventral clusters of aNSCs and niche glia, and mouse genetics to assess signature-driving gene contributions to regional identity. The R00 phase is mainly accomplished in Aim 3, where I build on my existing preliminary single cell RNA- sequencing analyses to gain mechanistic insight into functional heterogeneity among ependymal cells throughout the ventricular system. Together, these data will provide a foundational understanding of neurogenic niche signaling dynamics that together drive neurogenesis, and creates a new avenue of exploration to understand the diverse roles of ependymal cells at the brain/cerebral spinal fluid interface.

项目摘要/摘要： 大脑由高度专业化的神经元和神经胶质细胞组成，在空间上组织成不同的功能单元， 互连以执行自然界中一些最复杂的计算。迄今为止，尖端分子 遗传工具已被大量应用于神经结构和功能的研究。不太好 尽管放射状胶质细胞产生中枢神经系统中的所有神经元，但人们理解的是神经胶质细胞 在胚胎发育过程中。成体神经干细胞 (aNSC) 具有放射状胶质细胞的许多特征 星形胶质细胞在小鼠体内会在一生中产生新的神经元。 aNSC 存在于神经干细胞的侧壁中 侧脑室，位于复杂的细胞生态位中，调节其活动的许多特征。我们和其他人 之前发现 aNSC 的神经源潜力取决于 aNSC 在两条神经干细胞上的位置 心室壁的三维表面。背侧 aNSC 产生表层颗粒细胞 嗅球，而腹侧 aNSC 产生深层颗粒细胞。成人 NSC 神经源性潜能是细胞- 内在的，因为异位移植的细胞产生与其原始位置一致的神经元。然而， 指导性生态位细胞信号传导也可能是区域性定义的，最近的工作表明具有空间选择性 aNSC 直接或间接通过投射神经元响应进食行为而激活。鉴于 人们对脑修复干细胞疗法广泛感兴趣，但知识上的一个关键差距是缺乏机制 深入了解 aNSC 神经源性潜力和神经源性生态位区域化的分子决定因素。我 假设区域限制的转录特征定义了 aNSC 神经源性潜力，并且 生态位神经胶质细胞的互补特征是成人神经发生的区域特异性外在控制的基础。在这个 在提案中，我提出了跨越奖项的 K99 和 R00 阶段的三个正交目标。在前两个 目标主要在 K99 阶段完成，我使用单细胞测序来识别背侧和腹侧簇 aNSC 和小生境神经胶质细胞以及小鼠遗传学来评估签名驱动基因对区域身份的贡献。 R00 阶段主要在目标 3 中完成，我在现有的初步单细胞 RNA 的基础上进行构建 测序分析以获得室管膜细胞功能异质性的机制见解 整个心室系统。这些数据将共同提供对以下问题的基本理解： 神经源性生态位信号动力学共同驱动神经发生，并创造了一条新的途径 探索了解室管膜细胞在大脑/脑脊液界面的不同作用。