Inflammatory stressors in serotonergic brainstem dysfunction and SIDS

血清素能脑干功能障碍和 SIDS 中的炎症应激源

• 批准号: 10659327
• 负责人: ROBIN Lynn HAYNES
• 金额: $ 78.05万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659327
• 关键词: Address; Affect; Age; Animal Model; Apnea; Autopsy; Back to Sleep; Biological; Biological Markers; Biological Models; Bradycardia; Brain; Brain Stem; Breathing; Cause of Death; Cell model; Cells; Cerebrospinal Fluid; Chronic; Cluster Analysis; Data Set; Defect; Detection; Dinoprostone; Effectiveness; Embryo; Endothelial Cells; Engineering; Environmental Risk Factor; Event; Failure; Functional disorder; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Histology; Human; Hypoxia; IL17 gene; Impairment; In Situ Hybridization; Incidence; Infant; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injections; Interleukin-1 beta; Interleukin-2; Interleukin-4; Intervention; Kynurenine; Life; Link; Lipopolysaccharides; Maps; Mediator; Molecular; Mus; Neopterin; Neuroglia; Neurons; Oxygen; Pathology; Pathway interactions; Pattern; Physiological; Placental Insufficiency; Poly C; Poly I-C; Pregnancy; Prevention; Prevention strategy; Protocols documentation; RNA; Recovery; Reflex action; Research; Resolution; Risk; Risk Factors; Risk Reduction; Saline; Sampling; Serotonergic System; Serotonin; Serotonin Receptor 5-HT2A; Smoking; Source; Stress; Sudden Death; Sudden infant death syndrome; Testing; Tissues; Validation; Viral; Work; brain tissue; cell type; chemokine; cohort; comparison control; cytokine; experience; human tissue; in vivo; infant death; insight; intervention effect; neuroinflammation; normoxia; novel; novel therapeutic intervention; post-natal intermittent hypoxia; postnatal; postneonatal mortality; prevent; preventive intervention; pup; receptor binding; response; single nucleus RNA-sequencing; stressor; success

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.

项目摘要 婴儿猝死综合征（SIDS）仍然是美国新生儿后期死亡的主要原因， 尽管实施了安全的睡眠实践（外在风险降低），但这一事实仍然是不变的和毁灭性的。 解决这一世纪的健康危机现在需要发现内在的生物脆弱性， 可能导致生物标志物和预防性干预的合理分子途径。在多个 独立的SIDS组织数据集，脑干中的多巴胺能（5-HTergic）异常一致 在脑干5-HTergic活性降低的动物模型中， 观察到-小鼠幼仔从窒息性呼吸暂停和心动过缓循环中恢复的能力（类似于 在一些SIDS病例中观察到的呼吸暂停和心动过缓周期）显著减少。这样的5- HTergic系统功能障碍作为一种内在的脆弱性，可能由外在应激引起或加剧 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/或死前 感染.缺氧和感染都是SIDS的危险因素，并可增加神经炎症， AR受损。与对照组相比，一些SIDS病例中值得注意的新发现是 神经炎性标志物IL-1β、IL-2、IL-4、IL-17和GM-CSF和/或新蝶呤（Th 1的标志物 （促炎）细胞活化）。我们假设神经炎症， 由缺氧和/或死前感染（细菌或病毒）引发，相互作用产生脆弱的5- HTergic系统，降低AR的有效性，增加猝死的风险，并可能成为 一些婴儿猝死综合症病例我们建议：1）定量SIDS脑内的炎症介质， 介质谱是否与5-HTergic脑干异常有关。我们将检验这个假设 特异性炎症特征与低5-HT 1A和5-HT 2A受体结合和低5-HT水平相关。（二） 以单细胞分辨率绘制基因表达谱和总体细胞类型组成/状态的差异 SIDS病例（通过Aim 1确定的SIDS子集）和对照组的脑干组织。我们假设 SIDS亚群将通过神经胶质、神经元和/或内皮细胞中的特异性炎症特征来区分， 和基因表达差异将确定新的，以前未被识别的SIDS相关途径， 在细胞和动物模型中进行机械测试。3)评估慢性间歇性缺氧 （妊娠期至P8）和出生后死前感染对分子、细胞、炎症和生理 包括自动复苏反应（AR）。我们将检验一个假设， 死亡前缺氧和感染相互作用，产生更大的神经炎症，更严重的5-HTergic 缺陷，以及AR失败的可能性增加。SIDS研究 必须解决风险因素和死后病理学之间缺失的机械联系，以发展生命- 拯救干预。