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：
10063337
负责人：
STEVEN J SCHWULST
金额：
$ 4.63万
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/10063337
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 Expression Profiling 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.

项目摘要/摘要创伤性脑损伤（TBI）是一种日益增长且被低估的公共卫生威胁。疾病中心控制和伤害预防估计，每年有250万美国人承受创伤性脑损伤。在事实，与TBI相关的医疗保健每年要花费800亿美元。目前没有有效的疗法对于TBI和支持护理仍然是治疗的主要手段。 TBI的影响不仅强调了高死亡率，但也受生存遭受的重大长期神经系统障碍并发症。对TBI的免疫反应在随后的发展和发展中起着基本作用神经系统障碍，代表浸润单核细胞与住宅之间的复杂相互作用受伤的大脑的免疫系统 - 伴有膜。尽管如此，单核细胞和小胶质细胞知之甚少，并且驱动其相互作用的分子机制在很大程度上尚不清楚。初步工作已经产生了头部屏蔽的骨髓嵌合小鼠，允许明确的 TBI后的浸润单核细胞和小胶质细胞之间的分化。使用此模型，我们已经表明非古典单核细胞对于TBI之后的嗜中性粒细胞募集到受伤的大脑中至关重要有针对性的部署可改善受伤后的功能和解剖结局。此外，这个模型 TBI后允许分类孤立的小胶质细胞。这些的转录分析小胶质细胞在长期发展中实施了小胶质细胞基因表达的纵向变化神经退行性变化。两者合计，我们浸润的单核细胞塑造了小胶质细胞 TBI后对改变基因表达，解剖和功能结果的损伤的反应。测试这个假设假设，我们将确定小胶质细胞在TBI之后是否采用TBI相关表型以及是否采用它们的一代需要浸润的单核细胞。此外，我们的初步数据已确定在TBI小鼠小胶质细胞中涉及突触可塑性的基因的表达逐渐增加。在此，尤其是富含纹状体的蛋白酪氨酸磷酸酶（步骤）为关键蛋白过程。步骤在其他几种神经认知障碍中很重要，但在TBI中尚未研究。我们将确定步骤和其他突触可塑性的调节剂是否有助于发展和 TBI后使用敲除和转基因小鼠的神经认知功能障碍程度。最后，我们会的从创伤性脑损伤的人类患者中获得单核细胞，以开发人性化的小鼠模型 TBI。使用此模型，我们将确定TBI患者的单核细胞的自主变化是否直接与健康对照组的单核细胞相比，小胶质细胞采用TBI相关表型。共同拟议的研究将确定控制小胶质细胞和浸润的关键分子事件和途径 TBI中的单核细胞相互作用，从而增加了转化生物学发现和治疗的潜力 TBI患者的发育。