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

大多数脊髓损伤 (SCI) 研究项目的唯一目标是修复受伤的脊髓并恢复运动能力 功能。不幸的是，对于大多数 SCI 患者来说，恢复行走并不是优先考虑的事情 1。除了活动能力受损之外，SCI 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 器官系统病理学作为护理标准可以解释为什么 SCI 患者的生存率没有提高（相对于 2. 新出现的数据表明，脊髓损伤后，交感神经张力的丧失和 控制免疫器官（例如脾脏）和控制的主要器官的异常脊髓自主反射的发展 新陈代谢（例如肝脏、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功能障碍的发作和下游后果可以改善免疫和代谢 体内平衡。由于免疫和代谢过程通常紧密耦合并且对生命至关重要 3,4，因此很可能 大多数（如果不是全部）影响 SCI 个体的合并症（例如，肺部或皮肤自发感染、伤口愈合受损、 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) 解释为免疫代谢受损。本提案中的实验旨在研究 SCI 作为一种全身性疾病。 身体并将测试总体假设，即受伤后自主神经失调会破坏神经免疫稳态，从而产生一种状态 “神经源性元炎症”。该提案整合了当前资助的 NINDS R01 赠款和新想法。全部 实验和概念将建立在我的实验室过去使用“宏观”（系统和网络）和 研究神经免疫相互作用的病理生理学意义的“微观”（细胞到分子）工具。正如 美国国立卫生研究院 (NIH) 最近的举措强调，人类大脑疾病的治疗方法可能来自于更好地了解 大脑网络或回路，而不是单个大脑区域的缺陷，SCI 的治疗不太可能仅源于焦点 关于修复受伤的脊髓。

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.