Respiratory Rhythmogenesis and Chemosensitivity: A Genomic Approach

呼吸节律发生和化学敏感性：基因组方法

• 批准号: 8413411
• 负责人: KINGMAN PERKINS STROHL
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413411
• 关键词: A/J Mouse; Adult; Alleles; Animals; Apnea; Appearance; Automobile Driving; Behavior; Brain; Brain Stem; Breathing; Candidate Disease Gene; Chromosomes, Human, Pair 1; Chronic Obstructive Airway Disease; Continuous Positive Airway Pressure; Data; Development; Devices; Diabetes Mellitus; Diagnostic; Disease; Elements; Functional disorder; Generations; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genomics; Genotype; Goals; Heart failure; Human; Hypercapnia; Hypoxia; In Vitro; Knock-out; Link; Mechanics; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Nerve; Neurons; Obesity; Operative Surgical Procedures; Pathway interactions; Pattern; Pharmacotherapy; Phenotype; Physiology; Population; Process; Property; Proteins; Proteomics; Quantitative Trait Loci; Recombinant Inbred Strain; Recurrence; Relative (related person); Respiration Disorders; Rest; Risk Factors; SNP genotyping; Serotonin; Serotonin Agonists; Serotonin Antagonists; Single Nucleotide Polymorphism; Sleep; Sleep Apnea Syndromes; Slice; Stroke; Surveys; Syndrome; Testing; Time; Veterans; Wakefulness; Work; base; chronic neurologic disease; cohort; design; functional genomics; gene function; genetic linkage; genetic profiling; human disease; insight; interest; mRNA Expression; mouse model; novel; novel therapeutics; respiratory; response; trait; virtual

DESCRIPTION (provided by applicant): Respiratory rhythmogenesis is a term describing the processes for breath generation and patterning over time; abnormal rhythmogenesis carries consequences of hypoxia and hypercapnia, driving morbidity in conditions like sleep apnea, heart failure, stroke, and other chronic neurologic diseases. The C57Bl/6 (B6) mouse has inherent traits of pauses in breathing at rest and post-hypoxic periodic breathing (abnormal rhythmogenesis), localized to a ~50 Mb region on mouse Chromosome 1 which we call the Stab1 (for stability phenotype) QTL. The next step is to further define the functional genomic elements. Based on these novel findings, the hypotheses are that the stability phenotype (Stab1) trait and gene are correlated to hypoxic and/or hypercapnic responsiveness, and that the stability phenotype is expressed through brainstem circuits. Two interrelated aims expand the phenotype and genetic profiling through the opportunities afforded by publically available recombinant inbred strains (RISs) derived from DBA and B6 mouse strains in order to uncover the functions of Stab1 and other novel genes in respiratory rhythmogenesis, breath patterning, and chemosensitivity, in general. Aim 1 is designed to identify Stab1 candidate genes and functional proteins by 1) defining the association of the phenotypic trait of instability (number of pauses >1/minute during resting breathing and/or appearance of >3 cycles of periodic breathing following 2 minutes of hypoxia) with RIS genotypes relative to mRNA expression, and 2) comparing findings to hypoxic and and hypercapnic ventilatory responsiveness. To assess gene functions, we will link RIS genotype to global brainstem mRNA expression. The purpose here is to harness the power of these RISs which are already SNP genotyped, creating the opportunity for a virtual QTL linkage of SNPs to trait expression, and to use global mRNA expression (eQTL) and proteomics to test the hypothesis, identify novel molecular pathways involved in respiratory rhythmogenesis, and offer the opportunity for association studies in humans. Aim 2 will identify mechanisms producing breathing instability in in vitro brainstem slices. Studies test the hypotheses that 1) responses to serotonin agonists and antagonists and 2) responses to opiods, opiod antagonists, and NOS antagonists will disclose dynamic behaviors and circuit components which differ according to strain. The purpose is to utilize the discovery of the B6 instability phenotype as a platform to identify genomic contributions to breathing stability and respiratory control in general, with the long-term goal of mechanistically investigating how genes operate to produce abnormal ventilatory traits. Results from both Aims will inform the design of and priorities for sequencing of candidate genes, for understanding the current limitations of pharmacologic therapy, and for using genes as risk factors in human diseases of respiratory control.

描述（由申请人提供）： 呼吸节律发生是描述随着时间的推移呼吸产生和模式形成的过程的术语；节律发生异常会导致缺氧和高碳酸血症，从而导致睡眠呼吸暂停、心力衰竭、中风和其他慢性神经系统疾病等疾病的发病率。 C57Bl/6 (B6) 小鼠具有休息时呼吸暂停和缺氧后周期性呼吸（节律发生异常）的固有特征，定位于小鼠 1 号染色体上约 50 Mb 的区域，我们称之为 Stab1（稳定表型）QTL 。下一步是进一步定义功能基因组元件。基于这些新发现，假设稳定性表型 (Stab1) 性状和基因与缺氧和/或高碳酸血症反应相关，并且稳定性表型通过脑干回路表达。两个相互关联的目标通过来自 DBA 和 B6 小鼠品系的公开重组近交品系 (RIS) 提供的机会扩展表型和遗传分析，以揭示 Stab1 和其他新基因在呼吸节律发生、呼吸模式和化学敏感性中的功能， 一般来说。目标 1 旨在通过以下方式识别 Stab1 候选基因和功能蛋白： 1) 定义不稳定表型特征的关联（静息呼吸期间停顿次数 >1/分钟和/或 2 分钟后出现 >3 个周期性呼吸周期）缺氧）与 RIS 基因型相对于 mRNA 表达的关系，以及 2）将结果与缺氧和高碳酸血症通气反应性进行比较。为了评估基因功能，我们将 RIS 基因型与整体脑干 mRNA 表达联系起来。这里的目的是利用这些已经进行 SNP 基因分型的 RIS 的力量，为 SNP 与性状表达的虚拟 QTL 连锁创造机会，并使用全局 mRNA 表达 (eQTL) 和蛋白质组学来检验假设，识别新的分子参与呼吸节律发生的途径，并为人类关联研究提供了机会。目标 2 将确定在体外脑干切片中产生呼吸不稳定的机制。研究测试了以下假设：1）对血清素激动剂和拮抗剂的反应，2）对阿片类药物、阿片类拮抗剂和 NOS 拮抗剂的反应将揭示根据菌株而不同的动态行为和回路组件。目的是利用 B6 不稳定表型的发现作为平台，确定基因组对呼吸稳定性和呼吸控制的总体贡献，长期目标是从机制上研究基因如何产生异常通气特征。这两个目标的结果将为候选基因测序的设计和优先顺序提供信息，以了解当前药物治疗的局限性，以及使用基因作为人类呼吸控制疾病的危险因素。