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

项目概要/摘要 创伤性脑损伤 (TBI) 是一种日益严重且未被充分认识的公共卫生威胁。疾病中心 控制与伤害预防中心估计，每年有 250 万美国人遭受创伤性脑损伤。在 事实上，每年与 TBI 相关的医疗费用超过 800 亿美元。目前尚无有效疗法 对于 TBI 和支持治疗仍然是治疗的主要方法。 TBI 的影响不仅体现在其 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基础作用。 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 受伤大脑的免疫系统——小胶质细胞。尽管如此，单核细胞和单核细胞之间的相互作用 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 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 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 有针对性的消耗可以改善受伤后的功能和解剖结果。此外，该模型 允许在 TBI 后对孤立的小胶质细胞群体进行分类。这些的转录谱 小胶质细胞与长期发育过程中小胶质细胞基因表达的纵向变化有关 神经退行性改变。总而言之，我们认为浸润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。为了测试这个 假设 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 其生成需要浸润单核细胞。此外，我们的初步数据已确定 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。在 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。 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突触可塑性的发育和 使用基因敲除小鼠和转基因小鼠研究 TBI 后神经认知功能障碍的程度。最后，我们将 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 创伤性脑损伤。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 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。总的来说， 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。

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.