NOX酶活性对脊髓损伤中巨噬细胞活化的调节作用：年龄对损伤修复的影响

The overall goal of this proposal is to investigate age-related differences in functional recovery following spinal cord injury (SCI) and the underlying pathophysiological mechanisms, in order to provide potential cellular and molecular targets for developing effective therapeutic interventions to fully serve the SCI community. Epidemiological studies indicate that there is an increasing incidence of SCI among older population. Recent findings from our group demonstrated that 1) middle-aged mice exhibit worse functional deficits and exacerbated tissue damage, which may be associated with age-dependent increases of oxidative stress and pro-inflammatory macrophage activation following SCI; 2) the effectiveness of NOX inhibitor, apocynin, for SCI may be age-specific. In order to promote the translation of basic SCI research into clinical applications, there is an urgent need to include the factor of age in understanding the cellular and molecular mechanisms. In the current proposal, we hypothesize that age regulates macrophage activation and inflammatory response through alteration of NOX activity, thereby affecting tissue repair and functional recovery following SCI. We will incorporate animal behavioral tests, molecular and cell biology methods to test our hypothesis by finishing the following specific aims: .Aim 1: To determine the effect of inhibiting NOX enzyme activity on inflammatory response and repair after SCI in different age groups. .Aim 2: To determine that NOX activation on blood-derived macrophages is the key regulator mediating age-specific differences in recovery after SCI.

本课题旨在探索年龄对脊髓损伤修复的影响及病理生理机制，为开发针对不同年龄病患的临床治疗方案提供细胞和分子作用靶点。流行病学报告指出，中老年人群脊髓损伤发生率正大幅增加。我们的研究表明：老龄加剧炎性反应和氧化损伤，阻碍脊髓损伤后组织和功能的修复； NOX酶活性抑制剂apocynin在小鼠脊髓损伤中的治疗作用与年龄相关。为促进基础科研向临床应用转化，我们迫切需要将年龄因素纳入脊髓损伤研究，探索与年龄相关的细胞和分子作用机制。当前课题提出假设：年龄因素通过改变NOX酶活性来调控损伤脊髓中巨噬细胞的激活和炎性反应，从而影响组织修复和运动功能恢复。课题组将结合动物行为学、分子生物学、及细胞生物学等方法完成以下两个目标：1）明确抑制NOX酶活性对不同年龄脊髓损伤所导致的炎性反应及损伤修复的作用。2）明确血源性巨噬细胞及其NOX酶活性是介导脊髓损伤后年龄特异性修复差异的主导细胞及关键调节因子。

在当前中老年人群脊髓损伤发病率大幅增加，NOX 酶活性抑制剂对脊髓损伤的治疗作用具有年龄特异性背景下，为寻求脊髓损伤临床药物开发和治疗上的突破，我们将年龄因素纳入研究，深入探讨了年龄因素通过改变 NOX 酶活性调控损伤脊髓中巨噬细胞的激活和炎性反应，从而影响组织修复和运动功能恢复作用及机制。主要研究内容为：明确抑制 NOX 酶活性对不同年龄脊髓损伤所导致的炎性反应及损伤修复的作用；明确血源性巨噬细胞及其NOX酶活性是介导脊髓损伤后年龄特异性修复差异的主导细胞及关键调节因子。研究工作紧紧围绕“NOX酶活性对脊髓损伤中巨噬细胞活化的调节作用：年龄对损伤修复的影响”这个关键科学问题展开，并根据研究进展和面临问题及时进行针对性调整，最终完成了阐明年龄因素通过NOX酶活性来调控损伤脊髓中巨噬细胞的激活和炎性反应，从而影响组织修复和运动功能恢复这个研究目标。主要结果为：明确了1）不同年龄脊髓损伤中抑制NOX酶活性对参与炎性反应的炎症细胞的影响。2）不同年龄损伤脊髓中NOX酶活性对巨噬细胞表型及功能的调控。3）不同年龄脊髓损伤中NOX酶活性对血源性巨噬细胞募集到受损脊髓组织过程的影响。 4）血源性巨噬细胞是造成不同年龄脊髓损伤修复差异的主导细胞。5）不同年龄的巨噬细胞对NOX酶活性抑制调控作用的反应。本研究对帮助不同年龄层次的患者获得更好的治疗和康复提供了重要的理论依据。