Inflammatory stressors in serotonergic brainstem dysfunction and SIDS

项目摘要 婴儿猝死综合征(SIDS)仍是美国新生儿后死亡的主要原因--AN 尽管实施了安全睡眠做法(减少外部风险)，但事实是不变的和毁灭性的。 解决这场21世纪的健康危机现在需要发现内在的生物脆弱性和 可能导致生物标志物和预防性干预的看似合理的分子途径。在多个 独立的小岛屿发展中国家组织数据集，脑干中的5-羟色胺(5-HT)异常是一致的 在脑干5-羟色胺能活性降低的动物模型中，受损的自体复苏(AR) 观察-小鼠从窒息呼吸暂停和心动过缓的周期中恢复的能力(类似于 在一些小岛屿发展中国家中观察到的呼吸暂停和心动过缓的周期显著减少。该等5- 肝能系统功能障碍，作为一种内在的脆弱性，可由外在应激源引起或加重 例如出生前和/或出生后缺氧(例如，胎盘功能不全、父母吸烟)和/或生前 感染。缺氧和感染都是小儿麻痹症的危险因素，会增加神经炎症，这可能 损害AR。与对照组相比，在一些小岛屿发展中国家中值得注意的新发现是 神经炎性标志物IL-1、IL-2、IL-4、IL-17、GM-β和/或新喋呤(Th1的标志物 (促炎)细胞激活)在脑脊液中。我们假设神经炎症， 由缺氧和/或生前感染(细菌或病毒)触发，相互作用产生脆弱的5- 高能量系统，降低AR效果，增加猝死的风险，并可能是 一些小岛屿发展中国家的案例。我们建议：1)对小儿麻痹症脑内的炎症介质进行定量，并确定 一组介质是否与5-羟色胺能脑干异常有关。我们将检验这一假设 这种特殊的炎症特征与低5-HT1A和5-HT2A受体结合和低5-羟色胺水平有关。2) 在单细胞分辨率下绘制基因表达谱和整体细胞类型组成/状态的差异 小岛屿发展中国家病例(通过AIM 1确定的小岛屿发展中国家亚组)和对照的脑干组织。我们假设 SID亚群将通过胶质细胞、神经元和/或内皮细胞中特定的炎症特征来区分， 基因表达差异将识别以前未被识别的与小岛屿发展中国家相关的新途径 细胞和动物模型中的机械测试。3)评估慢性间歇性缺氧之间的相互作用 (妊娠至P8)和生前感染对分子、细胞、炎症和生理的影响 读数，包括自动复苏反应(AR)。我们将检验这样一种假设，即 生前缺氧和感染相互作用，造成更大的神经炎症，更严重的5-羟色胺 与单纯缺氧或感染相比，缺陷和AR失败的可能性增加。小岛屿发展中国家研究 必须解决风险因素和身体病理之间缺失的机械联系，以发展生命- 挽救干预措施。

Project Summary Sudden infant death syndrome (SIDS) remains the leading cause of post-neonatal mortality in the U.S.– an unchanging and devastating fact despite implementation of safe sleep practices (extrinsic risk reduction). Addressing this 21st century health crisis now requires discovery of intrinsic biological vulnerabilities and plausible molecular pathways that might lead to biomarkers and preventative interventions. In multiple independent SIDS tissue datasets, serotonergic (5-HTergic) abnormalities in the brainstem were consistently identified; in animal models of reduced brainstem 5-HTergic activity, compromised autoresuscitation (AR) was observed – the ability of mouse pups to recover from cycles of asphyxial apneas and bradycardia (resembling the cycles of apnea and bradycardia observed in some SIDS cases) was significantly diminished. Such 5- HTergic system dysfunction, as an intrinsic vulnerability, may be caused or exacerbated by extrinsic stressors such as pre- and/or postnatal hypoxia (e.g., placental insufficiency, parental smoking) and/or antemortem infections. Hypoxia and infection are each risk factors for SIDS and can increase neuroinflammation, which can impair AR. Notable new findings in some SIDS cases as compared to controls are elevations of the neuroinflammatory markers IL-1β, IL-2, IL-4, IL-17, and GM-CSF and/or in neopterin (a marker of Th1 (proinflammatory) cellular activation) in the cerebrospinal fluid. We postulate that neuroinflammation, triggered by hypoxia and/or antemortem infections (bacterial or viral), interact to create a vulnerable 5- HTergic system, reduce AR effectiveness, and increase the risk for sudden death, and may underlie some SIDS cases. We propose: 1) To quantitate inflammatory mediators within SIDS brains and determine whether a profile of mediators associates with 5-HTergic brainstem abnormalities. We will test the hypothesis that specific inflammatory profiles associate with low 5-HT1A and 5-HT2A receptor binding and low 5-HT levels. 2) To map at single-cell resolution, differences in gene expression profiles and overall cell-type composition/states of brainstem tissue across SIDS cases (the SIDS subsets identified through Aim 1) and controls. We hypothesize that SIDS subsets will be distinguished by specific inflammatory profiles in glia, neurons, and/or endothelial cells, and gene expression differences will identify novel, previously unrecognized SIDS-related pathways for mechanistic testing in cell and animal models. 3) Assess the interaction between chronic intermittent hypoxia (gestational to P8) and postnatal antemortem infection on molecular, cellular, inflammatory, and physiological readouts, including the autoresuscitation response (AR). We will test the hypothesis that the combined effects of antemortem hypoxia and infection interact to create greater neuroinflammation, more severe 5-HTergic deficits, and increased likelihood of AR failure, compared to either hypoxia or infection alone. SIDS research must address the missing mechanistic links between risk factors and postmortem pathology to develop life- saving interventions.