Respiratory Rhythmogenesis and Chemosensitivity: A Genomic Approach
呼吸节律发生和化学敏感性:基因组方法
基本信息
- 批准号:8413411
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:A/J MouseAdultAllelesAnimalsApneaAppearanceAutomobile DrivingBehaviorBrainBrain StemBreathingCandidate Disease GeneChromosomes, Human, Pair 1Chronic Obstructive Airway DiseaseContinuous Positive Airway PressureDataDevelopmentDevicesDiabetes MellitusDiagnosticDiseaseElementsFunctional disorderGenerationsGenesGeneticGenetic ModelsGenetic PolymorphismGenomicsGenotypeGoalsHeart failureHumanHypercapniaHypoxiaIn VitroKnock-outLinkMechanicsModelingMolecularMorbidity - disease rateMouse StrainsMusNerveNeuronsObesityOperative Surgical ProceduresPathway interactionsPatternPharmacotherapyPhenotypePhysiologyPopulationProcessPropertyProteinsProteomicsQuantitative Trait LociRecombinant Inbred StrainRecurrenceRelative (related person)Respiration DisordersRestRisk FactorsSNP genotypingSerotoninSerotonin AgonistsSerotonin AntagonistsSingle Nucleotide PolymorphismSleepSleep Apnea SyndromesSliceStrokeSurveysSyndromeTestingTimeVeteransWakefulnessWorkbasechronic neurologic diseasecohortdesignfunctional genomicsgene functiongenetic linkagegenetic profilinghuman diseaseinsightinterestmRNA Expressionmouse modelnovelnovel therapeuticsrespiratoryresponsetraitvirtual
项目摘要
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):
呼吸节律发生是一个描述呼吸产生和模式随时间变化的过程的术语;异常节律发生会导致缺氧和高碳酸血症,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。C57 B1/6(B6)小鼠具有休息时呼吸暂停和缺氧后周期性呼吸(异常节律发生)的固有特征,定位于小鼠1号染色体上的约50 Mb区域,我们称之为Stab 1(稳定性表型)QTL。下一步是进一步确定功能基因组元件。基于这些新的发现,假设是稳定性表型(Stab 1)性状和基因与低氧和/或高碳酸反应相关,并且稳定性表型通过脑干回路表达。两个相互关联的目标扩大了表型和遗传分析,通过提供的机会,从DBA和B6小鼠品系的重组近交系(RIS),以揭示Stab 1和其他新的基因在呼吸节律,呼吸模式,和化疗敏感性,一般的功能。目的1设计为通过以下方式鉴定Stab 1候选基因和功能蛋白:1)定义不稳定性的表型性状(在静息呼吸期间暂停次数>1/分钟和/或在缺氧2分钟后出现>3个周期性呼吸)与RIS基因型相对于mRNA表达的关联,和2)将结果与缺氧和高碳酸血症的呼吸反应性进行比较。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SNP基因分型的RISs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)和蛋白质组学来测试假设,识别参与呼吸节律发生的新分子途径,并为人类的关联研究提供机会。目的2将在体外脑干切片中确定产生呼吸不稳定的机制。研究测试了以下假设:1)对5-羟色胺激动剂和拮抗剂的反应和2)对阿片类药物、阿片类药物拮抗剂和NOS拮抗剂的反应将揭示根据应变而不同的动态行为和回路成分。其目的是利用B6不稳定表型的发现作为一个平台,以确定一般的呼吸稳定性和呼吸控制的基因组贡献,长期目标是机械地研究基因如何运作,以产生异常的呼吸性状。这两个目标的结果将为候选基因测序的设计和优先级提供信息,以了解目前药物治疗的局限性,并将基因用作人类呼吸控制疾病的风险因素。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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KINGMAN PERKINS STROHL其他文献
KINGMAN PERKINS STROHL的其他文献
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{{ truncateString('KINGMAN PERKINS STROHL', 18)}}的其他基金
A Tool for Neurotheraputic Therapy for Sleep Disordered Breathing
睡眠呼吸障碍的神经治疗工具
- 批准号:
9150622 - 财政年份:2015
- 资助金额:
-- - 项目类别:
A Tool for Neurotheraputic Therapy for Sleep Disordered Breathing
睡眠呼吸障碍的神经治疗工具
- 批准号:
9054568 - 财政年份:2015
- 资助金额:
-- - 项目类别:
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:
8244216 - 财政年份:2012
- 资助金额:
-- - 项目类别:
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 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Modeling of Pathogenic Breathing Pattern Dysregulation in Cardiopulmonary Disease
心肺疾病致病性呼吸模式失调的建模
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7864085 - 财政年份:2008
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Modeling of Pathogenic Breathing Pattern Dysregulation in Cardiopulmonary Disease
心肺疾病致病性呼吸模式失调的建模
- 批准号:
7557926 - 财政年份:2008
- 资助金额:
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Modeling of Pathogenic Breathing Pattern Dysregulation in Cardiopulmonary Disease
心肺疾病致病性呼吸模式失调的建模
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7155091 - 财政年份:2006
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