Divergent age-dependent peripheral innate immune response following TBI

TBI 后不同年龄依赖性外周先天免疫反应

基本信息

批准号：
10295232
负责人：
Michelle Lee Theus
金额：
$ 41.17万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10295232
关键词：
Acute Adolescent Adult Affect Age Attenuated Behavior Behavioral Biochemical Blood - brain barrier anatomy Blood Vessels Cells Cerebrovascular Circulation Chronic Data Endothelial Cells EphA4 Receptor Female Functional disorder Goals Health Hippocampus (Brain)Histologic IL4 gene Immune Immunologics In Vitro Infiltration Inflammation Inflammatory Injury Innate Immune Response Intervention Lesion Light Mediating Microglia Molecular Mus Neutrophil Activation Outcome Pathogenesis Pathogenicity Patients Peripheral Phagocytes Pharmacology Phenotype Physiological Process Publishing Recovery Recovery of Function Reporter Research Rodent Model Role Technology Testing Time Tissues Transgenic Mice Transgenic Organisms Traumatic Brain Injury Traumatic Brain Injury recovery age related aged behavioral phenotyping central nervous system injury disability drug discovery epigenomics functional outcomes genome-wide genome-wide analysis immunoregulation improved in vivo inflammatory milieu innovation macrophage male monocyte mouse model neuroinflammation neuron loss neuroprotection neurotoxic neurovascular neurovascular injury neutrophil new therapeutic target novel novel strategies porcine model pre-clinical preclinical study protective effect repaired response response to injury restoration transcriptomics

项目摘要

ABSTRACT Neuroinflammation has emerged as a critical component of secondary injury following brain trauma. Recent pre- clinical studies have shed light on the neurotoxic effects of peripheral-derived monocyte/macrophages (PDM). Our preliminary findings suggest this response may be dampened in the presence of juvenile-derived murine PDMs, however the cause of this neuroprotective response remains unknown. The research objective of this application is to characterize the cellular and molecular mechanism(s) underlying the divergent, age-dependent PDM response and their role in mediating neurovascular dysfunction following TBI. Our proposal builds upon extensive preliminary and published data demonstrating a distinct age-at-injury response following TBI. Juvenile- derived PDMs display reduced pro-inflammatory phenotype, and adult PDM depletion and replacement with those from juvenile mice confer neuroprotection. Moreover, we discovered that PDM-specific Tie2/EphA4 receptor crosstalk regulates their pro-inflammatory state across the age spectrum. We hypothesize that age- related differences in the PDM response underlie divergent outcomes following TBI. We will employ cell-specific depletions, and PDM replacement as well as novel transgenic murine models. These approaches will include rigorous behavioral, histological and innovative low-input genome-wide omics assessment of the relevance and mechanism(s) of PDM age on injury outcomes. We will also provide a framework for retooling the neuroinflammatory response to accelerate pro-recovery and dampen pro-inflammatory processes after TBI.

抽象的神经炎症已成为脑创伤后继发性损伤的关键组成部分。最近的前临床研究阐明了外周衍生的单核细胞/巨噬细胞（PDM）的神经毒性作用。我们的初步发现表明，在少年衍生的鼠存在下可能会抑制这种反应 PDM，但是这种神经保护反应的原因仍然未知。研究目标应用是表征依赖年龄依赖的基础的细胞和分子机制 PDM反应及其在TBI后介导神经血管功能障碍中的作用。我们的提议建立在广泛的初步和已发布的数据，表明TBI后有明显的年龄遭受损害的响应。少年- 派生的PDM显示出降低的促炎表型，成人PDM耗竭和替代少年小鼠赋予神经保护作用的人。此外，我们发现PDM特定的TIE2/EPHA4 受体串扰调节其在整个年龄范围内的促炎状态。我们假设这个年龄 TBI之后，PDM响应的相关差异是分歧的基础。我们将采用特定细胞耗竭，PDM替代以及新型的转基因鼠模型。这些方法将包括严格的行为，组织学和创新的低输入基因组的OMICS评估相关性和 PDM年龄在损伤结果上的机制。我们还将提供一个框架 TBI后，神经炎症反应对加速前恢复和抑制促炎过程。