Overcoming Neurogenic “Meta-Inflammation” to Promote Recovery After Spinal Cord Injury

大多数脊髓损伤(SCI)研究项目的单一目标是修复受伤的脊髓并恢复运动能力。 功能。不幸的是，对大多数脊髓损伤患者来说，恢复行走是一个较低的优先事项1。除了行动能力受损，脊髓损伤 导致全身器官系统缓慢而稳定的病理变化。未能识别和治疗多发性硬化症 作为护理标准的器官系统病理可能解释了为什么脊髓损伤患者的存活率没有提高(相对于 2.新出现的数据表明，脊髓损伤后，交感神经语调的丧失和 控制免疫器官(例如，脾)和控制主要器官的异常脊髓自主神经反射的发展 新陈代谢(如肝脏、肾上腺、肌肉、脂肪组织和肠道)会导致免疫功能障碍和多器官病理。 因此，减轻损伤后自主神经紊乱的发病和下游后果可以改善免疫和代谢。 动态平衡。由于免疫和新陈代谢过程通常是紧密耦合的，对生命3，4是必不可少的，因此很可能 影响脊髓损伤个体的大多数(如果不是全部)共病(例如，肺部或皮肤的自发性感染，伤口愈合受阻， 非酒精性脂肪性肝病(NAFLD)、慢性抑郁症、动脉粥样硬化、2型糖尿病、疲劳和焦虑)， 可以用免疫代谢受损来解释。本方案中的实验旨在将脊髓损伤作为一种疾病进行研究。 并将检验损伤后自主神经紊乱打破神经免疫动态平衡的总体假设，创造一种 “神经源性化生炎症”。这项提案整合了目前获得资金的NINDS R01赠款和新想法。全 实验和概念将建立在我的实验室过去的成功基础上，使用“宏观”(系统和网络)和 “微观”(细胞到分子)工具来研究神经免疫相互作用的病理生理学意义。就像 美国国立卫生研究院最近的倡议强调，人类大脑疾病的治疗很可能源于更好地理解 脑网络或脑回路，而不是单个大脑区域的缺陷，治疗脊髓损伤的方法不太可能只源于一个病灶 修复受伤的脊髓。

The singular goal of most spinal cord injury (SCI) research programs is to repair the injured spinal cord and restore locomotor function. Unfortunately, restoration of walking is a low priority for most SCI individuals 1. In addition to impaired mobility, SCI causes slow and steady pathological changes in organ systems throughout the body. Failure to recognize and treat multi- organ system pathology as a standard of care may explain why survival rates have not improved for SCI patients (relative to able-bodied individuals) over the past 30 years 2. Emerging data indicate that after SCI, the loss of sympathetic tone and the development of aberrant spinal autonomic reflexes that control immune organs (e.g., spleen) and the major organs that control metabolism (e.g., liver, adrenal gland, muscle, adipose tissue and gut) cause immune dysfunction and multi-organ pathology. Thus, mitigating the onset and downstream consequences of post-injury dysautonomia could improve immune and metabolic homeostasis. Since immune and metabolic processes are normally tightly coupled and are essential for life 3,4, it is likely that most, if not all, co-morbidities that affect SCI individuals (e.g., spontaneous infections in lung or skin, impaired wound healing, non-alcoholic fatty liver disease (NAFLD), chronic depression, atherosclerosis, type 2 diabetes, fatigue and anxiety), can be explained by impaired immunometabolism. Experiments in this proposal are designed to study SCI as a disease of the entire body and will test the overall hypothesis that post-injury dysautonomia breaks neuro-immune homeostasis creating a state of “neurogenic meta-inflammation”. This proposal is an integration of currently funded NINDS R01 grants and new ideas. All experiments and concepts will build on my lab's past successes using both “macroscopic” (systems and networks) and “microscopic” (cells to molecules) tools to study the pathophysiological significance of neuro-immune interactions. Just as recent NIH initiatives have emphasized that cures for human brain disease are likely to arise from better understanding of brain networks or circuits, rather than defects in a single brain region, a cure for SCI is unlikely to originate from a focus only on repairing the injured spinal cord.