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）：一种复发中央呼吸暂停的基因组方法可能会提供与原发性睡眠呼吸暂停综合症有关的致病见解，以及与复发性呼吸暂停和不稳定的呼吸相关的神经系统疾病。假设是，在缺氧的重氧后，在小鼠染色体1上自然存在的遗传变异是复发性apneas的表型。目的1是收集来自B6 x B6A1间互互相小鼠对的3代人的〜350只动物的周期性呼吸和DNA的表型数据。之所以选择此十字，是因为1个祖父母菌株（B6A1）通过将A/J染色体1取代在B6基因组上而失去了周期性呼吸（PB）表型。 AIM 2将是使用B6 x B6A1交配方案的前100个F2后代进行低分辨率链接扫描，以识别较小的小鼠染色体1的区域，该区域与周期性呼吸表型共聚。 AIM 3是在特定目标2中使用B6 x B6A1交配方案中的所有剩余动物进行高分辨率的连锁扫描，以罚款负责周期性呼吸的基因的位置。该阶段将以20个SNP/cm的近似分辨率来利用SNP标记。在AIM 4中，将将来自B6和A/J小鼠菌株的重组植物菌株（RL）的基因型和表型进行比较，以确认在特定目标2和3中确定的区域（S）作为周期性呼吸的调节剂中的特定目标调节剂，以预测染色体1的特定呼吸型信息，以预测其他小鼠均可能使用其他小鼠。鉴定小鼠中通气控制差异的遗传区域将洞悉对当前人类睡眠呼吸暂停药理学状态不良状态的功能网络，以及在其他医学和神经系统条件下观察到的呼吸不稳定的风险。