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

我们的大脑和免疫系统在整个身体中相互作用，以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。我们的免疫系统是在不断变化的-与我们的思想，感觉和行为高度一致。像创伤性脑损伤（TBI）这样具有破坏性的伤害对我们的思想，情感和行为产生长期影响并不奇怪。因此，有理由认为，TBI后免疫系统本身也会受到损害。事实上，实验和临床研究都显示了急性TBI患者的循环白细胞和血浆细胞因子水平的广泛变化。虽然这些措施作为有用的功能结果的相关性，这些变化的来源往往被忽视。骨髓（BM）造血干细胞（HSC）持续产生构成免疫系统的所有血细胞类型，可能使其成为神经免疫通讯的关键细胞效应子。因此，骨髓生态位的健康变化改变了我们免疫系统的组成，并对免疫力产生深远的影响。HSC的自我更新能力及其在体内的位置使其成为治疗操作的可行靶点。该提案的目的是了解TBI如何影响BM造血功能，进而了解外周免疫的下游变化如何影响TBI的进展。 通过跟踪慢性损伤小鼠随时间的结果并评估其对感染的反应，我们将确定TBI导致BM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BM嵌合体策略，以研究TBI诱导的BM功能变化的神经学后果以及这些变化是否可以自我纠正（目的1）。使用这种对慢性TBI潜在的神经免疫过程的全面描述，我们将确定BM HSC与脑损伤一起出错的分子机制（目的2），并在后期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，并改善慢性炎症（目的3）。这些目标的完成旨在揭示BM作为神经免疫轴的主要通信枢纽的作用，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子的作用。 为了进一步指导我的研究和职业发展，我将由经验丰富的导师和创伤性脑损伤，先天免疫和干细胞生物学专家组成的跨学科团队提供建议。这个导师的合奏将确保我的研究项目和职业发展的需要，通过频繁的会议和互动得到满足。我的总体职业目标是在一家大型研究机构担任独立调查员。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，并让我走上成为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.