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

我们的大脑和免疫系统通过整个身体进行健康和疾病的交流，但神经系统疾病是否会导致神经免疫交流的失败目前尚不清楚。我们的免疫系统是不断变化的——与我们的思想、感觉和行为高度一致。创伤性脑损伤（TBI）对我们的思想、感觉和行为产生长期影响，这并不奇怪。因此，免疫系统本身在创伤性脑损伤后也会受到损害。事实上，实验和临床研究都显示急性脑外伤患者循环白细胞和血浆细胞因子水平的广泛变化。虽然这些措施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（hsc）不断产生构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通讯的关键细胞效应器。因此，骨髓生态位健康的变化改变了我们免疫系统的组成，并对免疫产生深远的影响。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目标。本研究的目的是了解脑外伤如何影响脑梗死造血功能，反过来，外周免疫的下游变化如何影响脑外伤的进展。通过长期跟踪慢性损伤小鼠的结果并评估它们对感染的反应，我们将确定TBI导致脑屏障功能障碍、过早衰老和双向损伤的程度。我们将实施一种新的脑基嵌合体策略来研究脑外伤引起的脑基功能改变的神经学后果，以及这些改变是否可以自我纠正（目的1）。通过对慢性创伤性脑损伤的神经免疫过程的全面描述，我们将确定脑基质造血干细胞在脑损伤时发生差错的分子机制（目的2），并在晚时间点进行治疗干预，以消除衰老的小胶质细胞/巨噬细胞，恢复先天免疫，改善慢性炎症（目的3）。这些目标的完成旨在揭示脑脊髓炎作为神经免疫轴的主要通讯枢纽的作用，以及其祖细胞作为慢性炎症、免疫功能障碍和TBI疾病进展的主要效应因子。为了进一步指导我的研究和职业发展，我将接受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指导。这些导师将通过频繁的会议和互动，确保我的研究项目和职业发展需求得到满足。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奖将为实现这一目标提供跳板，使我能够发展自己的原创研究项目，并使我走上成为一名独立的早期研究者的道路。

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.