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

项目总结/摘要 创伤性脑损伤（TBI）是一种日益增长且未被充分认识的公共卫生威胁。中心疾病 控制和伤害预防估计，每年有250万美国人遭受创伤性脑损伤。在 事实上，TBI相关的医疗费用每年超过800亿美元。目前还没有有效的治疗方法 和支持性护理仍然是治疗的主要手段。TBI的影响不仅体现在其 死亡率高，而且幸存者遭受的长期严重神经功能障碍并发症。 对TBI的免疫应答在这种随后的TBI的发展和进展中起着重要作用。 神经功能障碍，并代表了浸润单核细胞和居民之间的复杂相互作用， 受损的脑小胶质细胞的免疫系统。尽管如此，单核细胞和 对小胶质细胞的了解很少，驱动它们相互作用的分子机制在很大程度上仍然未知。 初步工作已经产生了头部屏蔽骨髓嵌合小鼠，允许明确的 TBI后浸润单核细胞和小胶质细胞之间的分化。使用这个模型，我们已经证明， 非经典单核细胞对于中性粒细胞在TBI后募集到损伤的脑中是必不可少的， 靶向消耗导致损伤后改善的功能和解剖结果。此外，该模型 允许在TBI后分离小胶质细胞群体。这些基因的转录谱 小胶质细胞在长期的发育过程中涉及小胶质细胞基因表达的纵向变化， 神经退行性改变总之，我们认为浸润的单核细胞形成了小胶质细胞 TBI后对损伤的反应改变了基因表达、解剖学和功能结果。为了验证这一 假设 假设，我们将确定小胶质细胞是否在TBI后采用TBI相关表型， 浸润的单核细胞是其产生所必需的。此外，我们的初步数据已经确定， 在TBI小鼠的小胶质细胞中参与突触可塑性的基因的表达逐渐增加。在 特别地，纹状体富集蛋白酪氨酸磷酸酶（STEP）被鉴定为在此过程中的关键蛋白。 过程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发育， 使用基因敲除和转基因小鼠观察TBI后神经认知功能障碍的程度。最后，我们将 从创伤性脑损伤的人类患者获得单核细胞，以开发人源化的小鼠模型， 创伤性脑损伤使用这个模型，我们将确定TBI患者单核细胞的自主变化是否直接影响了TBI患者的免疫功能。 与来自健康对照的单核细胞相比，小胶质细胞采用TBI相关表型。总的来说， 这项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中单核细胞相互作用，从而提高了变革性生物发现和治疗的潜力。 TBI患者的发展。

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.