Mechanisms of injury-induced senescence and immune-sequelae in chronic TBI

我们的大脑和免疫系统相互作用，在健康和疾病中进行沟通，但神经系统疾病是否会导致神经免疫串扰失败，目前尚不清楚。我们的免疫系统在不断变化--与我们的思想、感觉和行为高度一致。毫不奇怪，像创伤性脑损伤(TBI)这样毁灭性的伤害会对我们的思想、感觉和行为产生长期的影响。因此，脑外伤后免疫系统本身也会受到损害，这是顺理成章的。事实上，实验和临床研究都表明，急性颅脑损伤患者的循环白细胞和血浆细胞因子水平发生了广泛的变化。虽然这些测量是功能结果的有用相关性，但这些变化的来源往往被忽视。骨髓(BM)造血干细胞(HSCs)持续产生组成免疫系统的所有血细胞类型，潜在地使它们成为神经免疫交流的关键细胞效应器。因此，骨髓生态位健康状况的变化会改变我们免疫系统的组成，并对免疫系统产生深远的影响。造血干细胞的自我更新能力和它们在体内的位置使它们成为治疗操作的可行靶点。这项建议的目的是了解脑外伤如何影响骨髓的造血功能，进而了解外周免疫的下游变化如何影响脑损伤的进展。通过跟踪慢性损伤小鼠随着时间的推移的结果并评估它们对感染的反应，我们将确定脑外伤导致骨髓功能障碍、过早衰老和双向损伤的程度。我们将实施一种新的骨髓嵌合体策略来研究脑外伤引起的骨髓功能改变的神经学后果，以及这些改变是否可以自我纠正(目标1)。利用对慢性脑损伤背后的神经免疫过程的全面描述，我们将确定骨髓造血干细胞在脑损伤中出错的分子机制(目标2)，并在后期进行治疗干预，以消除衰老的小胶质细胞/巨噬细胞，恢复先天免疫，并改善慢性炎症(目标3)。这些目标的完成试图揭示骨髓作为神经免疫轴的主要沟通枢纽的作用，以及其祖细胞作为慢性炎症、免疫功能障碍和脑外伤疾病进展的主要效应者的作用。为了进一步指导我的研究和职业发展，我将得到一个由创伤性脑损伤、先天免疫和干细胞生物学方面经验丰富的导师和专家组成的跨学科团队的建议。这组导师将确保我的研究项目和职业发展需求通过频繁的会议和互动得到满足。我的总体职业目标是成为一家大型研究机构的独立调查员。K奖将提供实现这一目标所需的跳板，允许我开发自己的原创研究计划，并使我走上成为一名独立的早期研究人员的道路。

Our brain and immune system interface throughout the body to communicate in health and disease, but whether neurological disease results as a failure of neuro-immune cross-talk is currently unknown. Our immune system is in constant flux- highly in tune with our thoughts, feelings, and behavior. It isn't surprising that an injury as devastating as a traumatic brain injury (TBI) has long-term consequences on our thoughts, feelings, and behavior. And so, it stands to reason that the immune system itself is also compromised after TBI. Indeed, experimental and clinical studies alike show widespread changes in circulating leukocytes and plasma cytokine levels of acute TBI patients. While these measures serve as useful correlates of functional outcome, the source of these changes is often overlooked. Bone marrow (BM) hematopoietic stem cells (HSCs) continuously give rise to all blood cell types that make up the immune system, potentially making them key cellular effectors of neuro-immune communication. Consequently, changes in the health of the bone marrow niche alter the composition of our immune system and have a profound impact on immunity. The self- renewing capacity of HSCs and their location in the body make them viable targets for therapeutic manipulation. The aim of this proposal is to understand how TBI affects BM hematopoietic function, and in turn, how downstream changes in peripheral immunity impact the progression of TBI. By tracking the outcome of chronically injured mice over time and assessing their response to infection we will ascertain the extent to which TBI causes BM dysfunction, premature senescence, and bidirectional impairment. We will implement a novel BM chimera strategy to study the neurological consequences of TBI- induced changes in BM function and whether these changes can be self-corrected (Aim 1). Using this comprehensive description of the neuro-immune processes underlying chronic TBI we will then determine the molecular mechanisms by which BM HSCs go awry with brain injury (Aim 2) and intervene therapeutically at late time points to eliminate senescent microglia/macrophages, restore innate immunity, and ameliorate chronic inflammation (Aim 3). The completion of these aims seeks to unmask the role of BM as a major communication hub of the neuro-immune axis, and its progenitor cells as the primary effectors of chronic inflammation, immune dysfunction, and TBI disease progression. To further guide my research and career development, I will be advised by an interdisciplinary team of experienced mentors and experts in traumatic brain injury, innate immunity, and stem cell biology. This ensemble of mentors will ensure my research project and career development needs are met through frequent meetings and interaction. My overall career goal is to be an independent investigator at a major research institution. The K award would provide the springboard required to reach this goal, allow me to develop my own original research program, and put me on a path to be an independent, early stage investigator.