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: 8598063
• 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/8598063
• 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）： 呼吸有节奏发生的术语描述了随着时间的流逝的呼吸产生和图案的过程。异常的节奏发生会带来缺氧和高碳水化合物的后果，在睡眠呼吸暂停，心力衰竭，中风和其他慢性神经系统疾病等疾病中推动发病率。 C57BL/6（B6）小鼠在静止和催眠后周期性呼吸（异常的节奏发生）时具有固有的停顿特征，该特征位于小鼠染色体上约50 MB区域的静止特征，我们称之为stab1（用于稳定性表型）QTL。下一步是进一步定义功能基因组元素。基于这些新的发现，假设是稳定性表型（Stab1）和基因与低氧和/或过度capnic反应性相关，并且稳定性表型通过脑干电路表达。两个相互关联的目的通过公开可用的重组近交菌株（RISS）提供的机会扩展了表型和遗传分析，从而揭示了Stab1和其他新型基因在呼吸节律的功能，呼吸含量，呼吸图案和化学意识上，从而揭示了Stab1和其他新型基因的功能。 AIM 1旨在通过1）定义不稳定性的表型特征（在静止呼吸中> 1/分钟的次数> 1/分钟的数量识别stab1候选基因和功能蛋白质（在静止呼吸中> 1/分钟的数量> 1/或出现）在低氧后2分钟后，周期性呼吸的周期性呼吸> 3个周期）与RIS型相对于MRNA表达的RIS型和2）与氧化物相比，以及2）与氧气相比和2）和氧化物的反应症。为了评估基因功能，我们将将RIS基因型与全球脑干mRNA表达联系起来。这里的目的是利用已经被SNP基因分型的Riss的力量，为SNP的虚拟QTL链接创造了特质表达的机会，并使用全球mRNA表达（EQTL）和蛋白质组学来检验假设，以确定与呼吸性节奏的新分子途径相关的新分子途径，并提供了与人类研究的机会。 AIM 2将确定在体外脑干切片中产生呼吸不稳定的机制。研究检验了1）对5-羟色胺激动剂和拮抗剂的反应以及2）对OPIOD，OPIOD拮抗剂和NOS拮抗剂的反应，将披露动态行为和电路成分，这些行为和电路成分根据菌株而有所不同。目的是利用B6不稳定性表型的发现作为一个平台，以确定对呼吸稳定性和呼吸控制的基因组贡献，其长期目标是机械地研究基因如何运作以产生异常的通气性质。两种目标的结果将为候选基因测序的设计和优先级提供信息，以了解药理治疗的当前局限性以及将基因用作呼吸控制人类疾病的危险因素。