Spatiotemporal Molecular Substrates of TBI at Single Cell Resolution

单细胞分辨率下 TBI 的时空分子底物

基本信息

批准号：
10386933
负责人：
Fernando Gomez-Pinilla
金额：
$ 56.46万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10386933
关键词：
Acute Address Affect Anxiety Atlases Behavior Biological Markers Brain Brain Concussion Brain region Cell Communication Cells Cellular Metabolic Process Chronic Cognitive Communities Complex Computer Models Data Dimensions Disease Dose Emotional Energy Metabolism Event Fluorescent in Situ Hybridization Functional disorder Gene Expression Regulation Genes Genomics Goals Heterogeneity Hippocampus (Brain)In Situ Individual Inflammation Injury Intervention Knowledge Learning Maps Measurement Memory Mental Depression Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Modernization Molecular Mus Neuronal Plasticity Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Pattern Peptides Pharmacodynamics Phase Population Post-Traumatic Stress Disorders Regulation Resolution Resources Role Site Social Behavior Sports Synaptic plasticity Systems Biology Technology Testing Therapeutic Time Traumatic Brain Injury Validation Yang brain cell cell type chronic traumatic encephalopathy cognitive process emotional behavior frontal lobe gene network high throughput technology humanin innovation insight mild traumatic brain injury multidisciplinary nervous system disorder network models neuropathology neurotransmission novel novel therapeutic intervention prevent response single cell technology single-cell RNA sequencing spatiotemporal transcriptome translational medicine treatment effect

项目摘要

Abstract Traumatic brain injury (TBI) has a complex neuropathology involving progressive alterations in brain centers that process cognitive and emotional behaviors and consist of heterogeneous cell populations. The complex spatiotemporal cell and molecular circuits underlying progressive TBI pathologies that can evolve into other disorders such as chronic traumatic encephalopathy and posttraumatic stress disorder remain to be understood. A comprehensive understanding of the molecular mechanisms underlying the complexity of TBI has been hindered by the lack of effective approaches to examine molecular events in individual brain cells that drive the overall pathology. We recently conducted a single cell resolution study of the hippocampus at the acute phase (24hr) of TBI using single cell RNA sequencing (scRNAseq) and revealed cell-type specific pathways and regulators of TBI. In particular, we found that depression of cell metabolism to be a key pathogenic component in the hippocampus at the acute phase of TBI. This finding suggests that tracking metabolic state of cells can be used to address key knowledge gaps on the spatial and time dependent progression of key pathologic drivers of TBI. Here we propose to test the hypothesis that cell metabolic regulators determine dynamic and spatial pathogenic pathways of TBI by harnessing the power of modern high-throughput technologies. We propose a highly integrative team approach to profit from recent advances in single cell RNA sequencing (scRNAseq) and multiplexed error robust fluorescent in situ hybridization (MERFISH) along with advanced gene-gene and cell-cell network modeling to inform on targets for intervention at specific time points or brain sites, a fundamental unsolved question in the TBI field. In Aim 1, we propose to utilize a unique combination of scRNAseq, MERFISH, and network modeling approaches to assess and validate the spatial and temporal vulnerability of each cell type to TBI in multiple brain regions at multiple time points in a data-driven, unbiased manner, which can inform us about hidden regulators of TBI pathogenesis. We will focus on the spatial and temporal changes in cellular metabolic pathways during TBI progression. Our preliminary results support that mt-Rnr2, encoding a mitochondrial peptide humanin and involved in cell metabolism, is a major site- and time-dependent driver of TBI. In Aim 2, we will functionally assess whether modulating mt-Rnr2 (humanin) has therapeutic potential to mitigate TBI pathology and prevent progression. We will also explore the cell-type specific mechanisms, especially the role of metabolism, underlying the actions of humanin. The overall goal of the proposal is to elaborate on an innovative strategy that can offer a comprehensive mechanistic understanding of the spatiotemporal cell substrates of TBI pathology and uncover novel targets and mechanisms to redirect the courses of TBI to overcome subsequent neurological disorders.

抽象的创伤性脑损伤（TBI）具有复杂的神经病理学，涉及大脑中心进行性改变该过程的认知和情感行为由异质细胞种群组成。综合体时空细胞和分子回路的进行性TBI病理学可以进化为其他诸如慢性创伤性脑病和创伤后应激障碍等疾病仍然是理解。对TBI复杂性基础的分子机制的全面理解缺乏检查单个脑细胞中分子事件的有效方法阻碍了这推动了整体病理。我们最近对海马的单细胞分辨率研究使用单细胞RNA测序（SCRNASEQ）的TBI急性相（24小时），并揭示了细胞类型的特异性 TBI的途径和调节剂。特别是，我们发现细胞代谢的抑郁是关键 TBI急性期海马中的致病成分。这一发现表明跟踪细胞的代谢状态可用于解决空间和时间依赖性的关键知识差距 TBI关键病理驱动因素的进展。在这里，我们建议测试细胞代谢的假设监管机构通过利用现代的力量来确定TBI的动态和空间致病途径高通量技术。我们提出了一种高度综合的团队方法，以从最近的进步中获利单细胞RNA测序（SCRNASEQ）和多路复用误差可靠的荧光原位杂交（Merfish）以及先进的基因基因和细胞网络网络建模，以告知干预目标在特定的时间点或大脑站点，这是TBI领域的基本未解决问题。在AIM 1中，我们建议利用scrnaseq，merfish和网络建模方法的独特组合来评估和验证多个大脑区域中每种细胞类型对TBI的空间和时间脆弱性以数据驱动的，公正的方式点，可以告知我们有关TBI发病机理的隐藏调节因子。我们将关注TBI进展过程中细胞代谢途径的空间和时间变化。我们的初步结果支持MT-RNR2编码线粒体肽人素并参与细胞代谢是TBI的主要地点和时间依赖的驱动因素。在AIM 2中，我们将在功能上评估是否调节MT-RNR2（Humanin）具有减轻TBI病理和预防进展的治疗潜力。我们还将探索细胞类型的特定机制，尤其是代谢的作用，是基础人类的行为。该提案的总体目标是阐述一种创新策略，该策略可以提供对TBI病理学的时空细胞底物的全面机械理解和发现重定向TBI课程以克服随后的神经系统疾病的新目标和机制。