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 婴儿猝死综合症（SIDS）仍然是美国昆虫后死亡率的主要原因 - 安全睡眠实践的不变和毁灭性的事实目的地实施（降低外部风险）。 解决这一21世纪的健康危机现在需要发现内在的生物学脆弱性和 合理的分子途径可能导致生物标志物和预防性干预。在多个 独立的SIDS组织数据集，脑干中的血清素能（5个握能）异常是一致的 确定；在减少脑干5止痛活性的动物模型中，自动震动（AR）为 观察到的 - 小鼠幼崽从沥青呼吸暂停和心动过缓的循环中恢复的能力（类似于 在某些SIDS病例中观察到的呼吸暂停和心动过缓的循环显着减少。这样的5- 外部系统功能障碍作为内在脆弱性，可能是由外部压力源引起或驱动的 例如产后和/或产后缺氧（例如，斑点功能不全，父母吸烟）和/或反植物 感染。缺氧和感染是小岛屿发展中国家的每个危险因素，可以增加神经炎症，这可以 损害AR。与对照组相比，在某些SIDS案例中，值得注意的新发现是 神经炎症标记物IL-1β，IL-2，IL-4，IL-17和GM-CSF和/或Neopterin（Th1的标记物） （促炎）细胞激活）在脑脊液中。我们假设神经炎症， 由缺氧和/或驱虫感染（细菌或病毒）触发，相互作用以创建脆弱的5-- HETGIC系统，降低AR效率并增加猝死的风险，并可能是 一些SIDS案件。我们提出：1）定量小米大脑内的炎症介体并确定 介体的概况是否与5次矫正脑干异常相关。我们将检验假设 该特异性炎症谱与低5-HT1A和5-HT2A受体结合和低5-HT水平相关。 2） 要以单细胞分辨率映射，基因表达谱和整体细胞类型组成/状态的差异 跨小链球菌病例的脑干组织（通过AIM 1鉴定的SIDS子集）和对照。我们假设 SIDS子集将通过神经胶质，神经元和/或内皮细胞中的特定炎症特征来区分 基因表达差异将确定新颖的，以前未被认可的SID相关的途径 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p8）和产后触角感染分子，细胞，炎症和生理 读数，包括自动响应响应（AR）。我们将测试合并效应的假设 抗质虫缺氧和感染相互作用以产生更大的神经炎症，更严重的5次疼痛 与仅缺氧或仅感染相比，缺陷和AR失败的可能性增加。 SIDS研究 必须解决风险因素与验尸后病理学之间缺失的机械联系 - 保存干预措施。