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The role of monocyte and microglia interaction in the evolution of traumatic brain injury-induced neurodegeneration

单核细胞和小胶质细胞相互作用在脑外伤引起的神经变性进化中的作用

基本信息

批准号：
10224682
负责人：
STEVEN J SCHWULST
金额：
$ 50.92万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224682
关键词：
Address Adopted Adoptive Transfer Affect Age American Anatomy Ankyrin Repeat Antigen Presentation Attenuated Automobile Driving B-Lymphocytes Behavioral Biological Bone Marrow Brain Brain Injuries Cell Separation Cells Centers for Disease Control and Prevention (U.S.)Cerebral Edema Chemosensitization Complex Corpus striatum structure Cytokine Receptors Data Development Disease Elements Engraftment Environment Event Evolution Fostering Frequencies Functional disorder Gene Expression Gene Expression Profile Gene Expression Profiling Generations Genetic Transcription Head Health Care Costs Health Expenditures Hematopoietic Histology Homeostasis Human Image Immune Immune response Immune system Immunologic Deficiency Syndromes Impairment Inflammation Inflammatory Inflammatory Response Injury Knockout Mice Knowledge Magnetic Resonance Imaging Mediating Memory Loss Microglia Modeling Molecular Molecular Profiling Morbidity - disease rate Morphology Mus Natural Killer Cells Natural regeneration Nerve Degeneration Neurocognitive Neurocognitive Deficit Neurologic Neutrophil Infiltration Outcome Pathway interactions Patients Phenotype Phosphoric Monoester Hydrolases Play Population Positron-Emission Tomography Prevention Process Protein Tyrosine Phosphatase Proteins Public Health Publishing Role Scaffolding Protein Secondary to Shapes Signal Transduction Sorting - Cell Movement Supportive care Survivors Synapses Synaptic plasticity T-Lymphocyte TBI treatment Testing Time Transcript Transgenic Mice Traumatic Brain Injury Up-Regulation Work brain cell cell type combat cytokine density effective therapy experimental study first responder functional outcomes healthy volunteer humanized mouse immune function improved injured injury prevention locomotor deficit macrophage monocyte mortality mouse model neurocognitive disorder neurocognitive test neurodegenerative phenotype novel therapeutics overexpression postsynaptic recruit repaired response response to brain injury response to injury synaptic function therapeutic development transcriptome sequencing transcriptomics wound healing

项目摘要

Project Summary/Abstract Traumatic brain injury (TBI) is a growing and under-recognized public health threat. The Centers for Disease Control and Injury Prevention estimate that 2.5 million Americans sustain a traumatic brain injury each year. In fact, TBI-related healthcare costs eclipse 80 billion dollars annually. There are currently no effective therapies for TBI and supportive care remains the mainstay of treatment. The impact of TBI is highlighted not only by its high mortality but also by the significant long-term neurologic impairment complications suffered by survivors. The immune response to TBI plays a fundamental role in the development and progression of this subsequent neurologic impairment and represents a complex interplay between infiltrating monocytic cells and the resident immune system of the injured brain—microglia. Despite this, reciprocal action between monocytes and microglia is poorly understood and the molecular mechanisms driving their interaction remain largely unknown. Preliminary work has generated head-shielded bone marrow chimeric mice allowing for the unambiguous differentiation between infiltrating monocytes and microglia after TBI. Using this model, we have shown that non-classical monocytes are essential for neutrophil recruitment into the injured brain after TBI and that their targeted depletion results in improved functional and anatomic outcomes after injury. Furthermore, this model has allowed for the sorting of isolated populations of microglia after TBI. Transcriptional profiling of these microglia has implicated longitudinal changes in microglial gene expression in the development of long-term neurodegenerative changes. Taken together, we that infiltrating monocytes shape the microglial response to injury altering gene expression, anatomic, and functional outcomes after TBI. To test this hypothesize hypothesis, we will determine whether microglia adopt a TBI-associated phenotype after TBI and whether infiltrating monocytes are required for their generation. Additionally, our Preliminary Data has identified progressively increased expression of genes involved in synaptic plasticity in the microglia of TBI mice. In particular, Striatal-enriched protein tyrosine phosphatase (STEP) was identified as a key protein in this process. STEP is important in several other neurocognitive disorders, but has not been investigated in TBI. We will determine whether STEP, and other regulators of synaptic plasticity, contribute to the development and degree of neurocognitive dysfunction after TBI with the use of knockout and transgenic mice. Lastly, we will obtain monocytes from traumatically brain-injured human patients to develop a humanized mouse model of TBI. Using this model, we will determine whether autonomous changes in monocytes from TBI patients direct microglia to adopt a TBI-associated phenotype as compared to monocytes from healthy controls. Collectively, the proposed studies will identify key molecular events and pathways that govern microglia and infiltrating monocyte interaction in TBI, thus raising the potential for transformative biologic discovery and therapeutic development in TBI patients.

项目总结/文摘