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

项目摘要/摘要 创伤性脑损伤(TBI)是一种日益严重但尚未得到充分认识的公共健康威胁。美国疾病控制中心 控制和伤害预防组织估计，每年有250万美国人遭受创伤性脑损伤。在……里面 事实上，与脑外伤相关的医疗成本每年超过800亿美元。目前还没有有效的治疗方法 对于创伤性脑损伤，支持性护理仍然是治疗的主要手段。TBI的影响不仅体现在它的 高死亡率还由幸存者长期遭受的严重神经损伤并发症所致。 对脑损伤的免疫反应在随后的脑损伤的发生和发展中起着基础性的作用。 神经损害，代表了浸润性单核细胞和居住者之间的复杂相互作用 损伤脑的免疫系统--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也在很大程度上仍不清楚。 初步工作已经产生了头保护的骨髓嵌合小鼠，允许明确的 颅脑损伤后浸润性单核细胞与小胶质细胞的分化。使用这个模型，我们已经证明了 非经典单核细胞是颅脑损伤后中性粒细胞重新聚集到受损脑内所必需的，它们的 靶向耗竭可改善损伤后的功能和解剖结果。此外，该模型还具有较高的效率 允许在脑损伤后对分离的小胶质细胞群体进行分类。这些基因的转录特征 小胶质细胞在长期发展过程中涉及到小胶质细胞基因表达的纵向变化 神经退行性改变。总之，我们这些正在渗透的单核细胞塑造了小胶质细胞 颅脑损伤后对损伤的反应改变基因表达、解剖和功能结果。为了测试这一点 假设 假设，我们将确定小胶质细胞是否在脑损伤后采用与脑损伤相关的表型，以及 浸润性单核细胞是其生成所必需的。此外，我们的初步数据显示， 脑损伤小鼠小胶质细胞突触可塑性相关基因表达的进行性增加。在……里面 特别是，纹状体富含蛋白酪氨酸磷酸酶(STEP)被确定为其中的关键蛋白质 进程。STEP在其他几种神经认知障碍中也很重要，但尚未在脑损伤中进行研究。 我们将确定STEP和其他突触可塑性的调节因子是否有助于突触的发育和 使用基因敲除和转基因小鼠的脑损伤后神经认知功能障碍的程度。最后，我们将 从脑外伤患者中获取单核细胞以建立人源化的小鼠脑损伤模型 TBI。利用这一模型，我们将确定脑外伤患者单核细胞的自主变化是否直接 与来自健康对照组的单核细胞相比，小胶质细胞采用与脑外伤相关的表型。总而言之， 拟议的研究将确定控制小胶质细胞和渗透的关键分子事件和途径。 脑外伤中单核细胞的相互作用，从而提高了变革性生物发现和治疗的潜力 颅脑损伤患者的发展。

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.