An in vivo screen for genes underlying protective neonate respiratory reflexes to identify potential contributors to Sudden Infant Death Syndrome and other congenital respiratory pathophysiologies

体内筛选保护性新生儿呼吸反射的基因，以确定婴儿猝死综合症和其他先天性呼吸病理生理学的潜在因素

• 批准号: 10531622
• 负责人: Russell S Ray
• 金额: $ 70.28万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531622
• 关键词: 1 year old; Adult; Air; Anoxia; Apnea; Bradycardia; Brain Stem; Breathing; Carbon Dioxide; Cause of Death; Cell physiology; Cessation of life; Characteristics; Computer software; DNA Sequence Alteration; Data; Data Analyses; Development; Diagnostic; Embryo; Etiology; Exposure to; Failure; Foundations; Functional disorder; Gases; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Screening; Goals; Heart Rate; Heterozygote; Homeostasis; Human; Hypoxia; Imaging Techniques; In Situ Hybridization; Infant; International; Joubert syndrome; Knock-out; Laboratories; Link; Measurement; Medicine; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Neonatal Mortality; Nervous System; Neuroanatomy; Neurologic; Neurophysiology - biologic function; Outcome; Pattern; Perinatal; Perinatal mortality demographics; Phenotype; Physiological; Pitt-Hopkins syndrome; Positioning Attribute; Production; Reflex action; Respiration; Respiration Disorders; Respiratory physiology; Resuscitation; Rett Syndrome; Robotics; Sensory; Series; Sudden infant death syndrome; Syndrome; System; Therapeutic; brain abnormalities; causal variant; college; congenital central hypoventilation syndrome; congenital respiratory disorder; data analysis pipeline; developmental disease; feature detection; in vivo; innovation; knock out mouse project; loss of function mutation; molecular marker; mouse genome; mutant; neonate; neural network; novel; prophylactic; respiratory; respiratory hypoxia; respiratory reflex; screening; stem; transcriptome sequencing

PROJECT SUMMARY ABSTRACT The goal of this proposal is to identify genes that are required for neuro-developmental and cellular processes critical to protective neonate respiratory reflexes that may be perturbed in Sudden Infant Death Syndrome (SIDS) and other congenital respiratory pathophysiologies. To that end, we are in a unique position to leverage the Baylor College of Medicine (BCM) Knockout Mouse Project-2 (KOMP2)/International Mouse Phenotyping Consortium (IMPC) efforts to knock out or mutate and characterize every gene in the mouse genome. The BCM KOMP2/IMPC effort is focused on adult as well as some embryonic and perinatal top-level phenotyping. However, this effort does not systematically or deeply evaluate adult or neonate respiration. Thus, we aim to leverage the BCM KOMP2/IMPS knockout production and phenotyping pipeline to identify genes critical to the development and function of neural networks in neonate respiration. The hypercapnic and hypoxic ventilatory reflexes are hypothesized to be perturbed in SIDS and several other congenital respiratory disorders. Failure of the neonate auto-resuscitation reflex is thought to be a common end point for many SIDS cases. Therefore across two aims, we propose to screen KOMP2 mutant mouse lines to identify novel genes involved in the development and function of protective neonate respiratory reflexes including 1) the hypercapnic and hypoxic ventilatory reflexes; 2) and the neonate auto-resuscitation reflex; 3) followed by an initial neuro-anatomical characterization of cellular, molecular and genetic markers in the mutants. To achieve the high throughput capacity and precision needed to screen sufficient numbers of mutant lines and gain meaningful results, we have developed a novel robotic closed loop automated neonate respiratory platform and data analysis pipeline. The proposed phenotyping pipeline will enable a multifaceted characterization of genes that when homozygously or heterozygously mutated, disrupt critical protective neonate respiratory reflexes. The successful outcomes will deliver a suite of genes that provide a foundation for additional studies to yield important clues about the genetic, molecular, cellular processes that underly respiratory neural network development and function in neonates as well as inform upon the mechanistic underpinnings of congenital pathophysiologies such as SIDS, CCHS, Rett Syndrome and others.

项目摘要 这项计划的目标是确定神经发育和细胞过程所需的基因 对保护性新生儿呼吸反射至关重要，这可能会在婴儿猝死综合征中受到干扰 （SIDS）和其他先天性呼吸道病理生理学。为此，我们处于一个独特的地位， 贝勒医学院（Baylor College of Medicine，简称BLM）基因敲除小鼠项目-2（KOMP 2）/国际小鼠表型分析 IMPC致力于敲除或突变小鼠基因组中的每一个基因并对其进行表征。的 ESTKOMP 2/IMPC的工作重点是成人以及一些胚胎和围产期的顶级表型。 然而，这项工作并没有系统地或深入地评估成人或新生儿的呼吸。因此，我们的目标是 利用ESTK 0 MP2/IMPS敲除生产和表型分析管道来鉴定对基因表达至关重要的基因。 新生儿呼吸中神经网络的发育和功能。 高碳酸血症和缺氧性反射被假设为在SIDS和其他几种先天性 呼吸系统疾病新生儿自动复苏反射失败被认为是许多人的常见终点 婴儿猝死综合症病例。因此，在两个目标，我们建议筛选KOMP 2突变小鼠品系，以确定新的基因 参与保护性新生儿呼吸反射的发育和功能，包括1）高碳酸血症和 缺氧性呼吸反射; 2）和新生儿自动复苏反射; 3）随后进行初始神经解剖学检查 突变体中的细胞、分子和遗传标记的表征。为了实现高吞吐量， 为了筛选足够数量的突变株系并获得有意义的结果，我们开发了一种新的 机器人闭环自动化新生儿呼吸平台和数据分析管道。 所提出的表型分析管道将使基因的多方面表征成为可能， 异源突变，破坏关键的保护性新生儿呼吸反射。成功的结果将带来一个 一套基因，为进一步的研究提供了基础，以产生关于遗传，分子， 新生儿呼吸神经网络发育和功能的细胞过程，以及提供信息 诸如SIDS、CCHS、Rett综合征等先天性病理生理学的机制基础。