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: 10342442
• 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/10342442
• 关键词: 1 year old; Adult; Air; Anatomy; 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; Homeostasis; Human; Hypoxia; Imaging Techniques; In Situ Hybridization; Infant; International; Joubert syndrome; Knock-out; Knockout Mice; Laboratories; Link; Measurement; Medicine; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Neonatal Mortality; Nervous system structure; Neurologic; Neurophysiology - biologic function; Outcome; Pattern; Perinatal; Perinatal mortality demographics; Phenotype; Physiological; Pitt-Hopkins syndrome; Play; Positioning Attribute; Production; Reflex action; Respiration; Respiration Disorders; Respiratory physiology; Resuscitation; Rett Syndrome; Robotics; Role; Series; Sudden infant death 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; 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.

项目总结摘要 这项提议的目标是确定神经发育和细胞过程所需的基因。 在婴儿猝死综合征中可能受到干扰的保护性新生儿呼吸反射的关键 (小岛屿发展中国家)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，可以利用 贝勒医学院(BCM)基因敲除小鼠项目-2(KOMP2)/国际小鼠表型 IMPC(IMPC)致力于敲除或突变小鼠基因组中的每一个基因并确定其特征。这个 BCM KOMP2/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，这一努力并没有系统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BCM KOMP2/IMPS基因敲除生产和表型测定流水线来识别与 神经网络在新生儿呼吸中的发展和作用。 高碳酸血症和低氧的呼吸性反射被认为是小儿麻痹症和其他几种先天性疾病的干扰因素。 呼吸系统疾病。新生儿自动复苏反射的失败被认为是许多人的共同终点 小岛屿发展中国家的案例。因此，我们建议跨越两个目标，筛选KOMP2突变小鼠系来识别新的基因 参与新生儿保护性呼吸反射的发育和功能，包括1)高碳酸血症和 低氧呼吸反射；2)和新生儿自动复苏反射；3)随后进行初始神经解剖 突变体的细胞、分子和遗传标记的特征。实现高吞吐能力和 为了筛选足够数量的突变系并获得有意义的结果所需的精确度，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流水线。 建议的表型流水线将使基因的多方面表征成为可能，当纯合子或 杂合突变，扰乱了关键的新生儿保护性呼吸反射。成功的结果将带来一个 一套基因，为进一步的研究提供基础，以产生关于遗传，分子， 支持新生儿呼吸神经网络发育和功能的细胞过程以及 先天性病理生理学的机制基础，如小儿麻痹症、CCHS、Rett综合征和其他。