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Spatiotemporal Molecular Substrates of TBI at Single Cell Resolution

单细胞分辨率 TBI 的时空分子底物

基本信息

批准号：
10606498
负责人：
Fernando Gomez-Pinilla
金额：
$ 55.3万
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/10606498
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 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 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.

摘要