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：
10460647
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/10460647
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.

项目概要/摘要创伤性脑损伤 (TBI) 是一个日益严重且未被充分认识的公共卫生威胁。控制和伤害预防中心估计，每年有 250 万美国人遭受创伤性脑损伤。事实上，每年与 TBI 相关的医疗费用超过 800 亿美元，目前尚无有效的治疗方法。 TBI 的影响和支持治疗仍然是治疗的支柱 TBI 的影响不仅体现在其治疗上。死亡率高，而且幸存者遭受严重的长期神经损伤并发症。 TBI 的免疫反应在随后的 TBI 的发生和进展中发挥着重要作用。神经系统损伤，代表浸润单核细胞和居民之间复杂的相互作用尽管如此，单核细胞和小胶质细胞之间的相互作用仍然存在。人们对小胶质细胞知之甚少，驱动它们相互作用的分子机制仍然很大程度上未知。初步工作已经产生了头部屏蔽的骨髓嵌合小鼠，可以明确地使用该模型，我们发现 TBI 后浸润性单核细胞和小胶质细胞之间的分化。非经典单核细胞对于 TBI 后将中性粒细胞募集到受伤大脑中至关重要，并且它们的靶向消耗可改善损伤后的功能和解剖结果。允许在 TBI 后对分离的小胶质细胞群体进行转录分析。小胶质细胞在长期发育过程中涉及小胶质细胞基因表达的纵向变化总而言之，我们认为浸润性单核细胞塑造了小胶质细胞。 TBI 后对损伤的反应会改变基因表达、解剖学和功能结果。已保存假设，我们将确定小胶质细胞是否在 TBI 后采用与 TBI 相关的表型，以及是否此外，我们的初步数据已确定其生成需要浸润单核细胞。 TBI 小鼠小胶质细胞中参与突触可塑性的基因表达逐渐增加。特别是，纹状体富含酪氨酸磷酸酶（STEP）被认为是这一过程中的关键蛋白质。 STEP 在其他几种神经认知障碍中很重要，但尚未在 TBI 中进行研究。我们将确定 STEP 和其他突触可塑性调节因子是否有助于突触可塑性的发育和最后，我们将使用基因敲除小鼠和转基因小鼠来研究 TBI 后神经认知功能障碍的程度。从脑部受伤的人类患者身上获取单核细胞，以开发人源化小鼠模型使用该模型，我们将确定 TBI 患者单核细胞的自主变化是否直接影响总体而言，与健康对照的单核细胞相比，小胶质细胞采用与 TBI 相关的表型。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，从而提高了变革性生物学发现和治疗的潜力 TBI 患者的发展。