Overcoming neurogenic “meta-inflammation” to promote recovery after spinal cord injury

克服神经源性“元炎症”以促进脊髓损伤后的恢复

• 批准号: 9924658
• 负责人: PHILLIP G POPOVICH
• 金额: $ 109.71万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9924658
• 关键词: Adipose tissue; Adrenal Glands; Affect; Anxiety; Atherosclerosis; Brain; Brain Diseases; Brain region; Cells; Coupled; Data; Defect; Development; Disease; Dysautonomias; Failure; Fatigue; Funding; Goals; Grant; Homeostasis; Human; Immune; Immune System Diseases; Impaired wound healing; Impairment; Individual; Infection; Inflammation; Injury; Life; Liver; Lung; Metabolic; Metabolism; Microscopic; Muscle; National Institute of Neurological Disorders and Stroke; Neuroimmune; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pathologic; Pathology; Quality of life; Recovery; Recovery of Function; Reflex control; Research; Skin; Spinal; Spinal cord injury; Spinal cord injury patients; Spleen; Survival Rate; System; Testing; United States National Institutes of Health; Walking; autonomic reflex; body system; chronic depression; comorbidity; design; experimental study; improved; injury and repair; non-alcoholic fatty liver disease; novel; programs; restoration; standard of care; success; tool

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.

大多数脊髓损伤（SCI）研究项目的单一目标是修复受损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，恢复行走是一个低优先级1。除了运动障碍，SCI 导致全身器官系统缓慢而稳定的病理变化。不承认和对待多- 器官系统病理学作为标准治疗可以解释为什么SCI患者的存活率没有提高（相对于 （二）过去30年来。新出现的数据表明，SCI后，交感神经张力的丧失和 控制免疫器官的异常脊髓自主反射的发展（例如，脾）和控制的主要器官 代谢（例如，肝脏、肾上腺、肌肉、脂肪组织和肠）引起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是紧密耦合的，并且是生命所必需的3，4，因此很可能 大多数（如果不是全部）影响SCI个体的共病（例如，肺部或皮肤自发性感染，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）， 可以用免疫代谢受损来解释在这个建议中的实验是为了研究SCI作为一种疾病的整体 身体，并将测试整体假设，即损伤后自主神经功能障碍打破神经免疫稳态， “神经源性炎症”。该提案是目前资助的NINDS R 01赠款和新想法的整合。所有 实验和概念将建立在我的实验室过去的成功使用“宏观”（系统和网络）， “微观”（细胞到分子）工具，以研究神经免疫相互作用的病理生理意义。正如 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可能来自于更好地了解 大脑网络或回路，而不是单一大脑区域的缺陷，SCI的治疗不太可能仅仅源于一个焦点 修复受损的脊髓