Genetic Mechanisms for Central Apneas

中枢性呼吸暂停的遗传机制

• 批准号: 7104670
• 负责人: KINGMAN PERKINS STROHL
• 金额: $ 14.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104670
• 关键词: chromosomes; genes; genetics; phenotype; pulmonary respiration; sex partner

DESCRIPTION (provided by applicant): A genomic approach to recurrent central apneas might provide pathogenic insight relevant to primary sleep apnea syndromes and neurological conditions associated with recurrent apneas and unstable breathing. The hypothesis is that naturally occurring genetic variations on mouse chromosome 1 underlie a phenotype of recurrent apneas following reoxygenation from hypoxia. Aim 1 is to collect phenotype data on periodic breathing and DNA from~350 animals from 3-generational pedigrees derived from pairs of B6 x B6a1 intercross mice. This cross has been selected because 1 grandparent strain (b6a1) has lost the periodic breathing (PB) phenotype through substitution of A/J chromosome 1 onto the B6 genome. Aim 2 will be to conduct a low resolution linkage scan using the first 100 F2 offspring from the B6 x B6a1 mating scheme to identify a smaller region(s) of mouse chromosome 1 that co-segregates with the periodic breathing phenotype. Aim 3 is to perform a high resolution linkage scan on the region(s) identified in Specific Aim 2 using all remaining animals from the B6 x B6a1 mating scheme to fine map the location of the gene(s) responsible for the periodic breathing. This phase will utilize SNP markers at an approximate resolution of 20 SNPs/cM across the region(s) of interest. In Aim 4, genotypes and phenotypes from recombinant inbred strains (Rl) derived from the B6 and A/J mouse strains will be compared to the mapping results to confirm the region(s) identified in Specific Aims 2 and 3 as modulators for periodic breathing, and strain-specific haplotype information for chromosome 1 will be used to predict which other mouse strains are likely to have periodic breathing. Identification of genetic regions that contribute significantly to the variance in ventilatory control in the mouse will give insight into functional networks informative to the current poor state of pharmacology for human sleep apnea, and for the risks of breathing instability observed in other medical and neurological conditions.

描述（由申请人提供）：复发性中枢性呼吸暂停的基因组方法可能提供与复发性呼吸暂停和不稳定呼吸相关的原发性睡眠呼吸暂停综合征和神经系统疾病相关的病原性见解。假设是小鼠1号染色体上自然发生的遗传变异是缺氧再氧后复发性呼吸暂停表型的基础。目的1是收集来自B6 x B6a1杂交小鼠3代谱系的约350只动物的周期性呼吸和DNA表型数据。之所以选择这一杂交品种，是因为1个外祖菌株（b6a1）通过将A/J染色体1替换到B6基因组上而失去了周期性呼吸（PB）表型。目标2将使用来自B6 x B6a1交配方案的前100个F2后代进行低分辨率连锁扫描，以确定与周期性呼吸表型共分离的小鼠1号染色体的较小区域。目标3是使用来自B6 x B6a1交配方案的所有剩余动物，对特定目标2中确定的区域进行高分辨率连锁扫描，以精细绘制负责周期性呼吸的基因位置。这一阶段将在感兴趣的区域内以大约20个SNP /cM的分辨率使用SNP标记。在目标4中，来自B6和A/J小鼠菌株的重组自交系（Rl）的基因型和表型将与定位结果进行比较，以确认在特定目标2和3中确定的区域是周期性呼吸的调节剂，并且1号染色体的菌株特异性单倍型信息将用于预测哪些其他小鼠菌株可能具有周期性呼吸。识别对小鼠通气控制差异有重要影响的遗传区域，将有助于深入了解功能网络，为当前人类睡眠呼吸暂停的不良药理学状态提供信息，并为在其他医学和神经系统疾病中观察到的呼吸不稳定风险提供信息。