GENETICS OF AIRWAY RESPONSIVENESS

根据目前可用的数据，我们认为呼吸道反应性 是哮喘病变的独立数量性状，即 在基因控制下。众所周知，呼吸道的可变性 在给定品系的近交系小鼠中的反应性很小，而 不同菌株之间的呼吸道反应性差异很大。 呼吸道中存在与菌株相关的表型变异 小鼠的反应性表明，遗传位点可能 可以确定对呼吸道反应性负有具体责任 通过适当的基因研究。扩展版的可用性 用于鼠标的染色体图，用于跟踪多个 在数量上对给定基因有贡献的基因座 表型性状和进行分子遗传作图的能力 对少量血液的高分辨率，现在使其成为可能 确定数量性状的遗传连锁。 呼吸道对乙酰甲胆碱和5-羟色胺(5-羟色胺)的反应性 羟色胺)，由减少肺活量所需的输注剂量所示。 电导(GL)50%将在A/J、C57BL/6、C57BL/6xA/J中确定 由这些祖细胞衍生的F1和重组近交系(RI)小鼠 菌株。响应性数据将接受分析，以 确定一个或多个基因位点是否影响呼吸道 对每个调解人的反应，以及是否存在共同的位置 影响呼吸道对两种介质的反应性。曾经的模式 遗传及其单基因或多基因性质是建立在小鼠来源的 将使用多态标记对适当的杂交组合进行基因分型 以10厘米的间隔跨越基因组。数据将受到链接的影响 使用一种允许考虑单个或 多基因对呼吸道表型表达的影响 响应性是一种数量性状。特别是，联系将是 在多态标记的遗传模式和 呼吸道反应性表型。候选基因座，通过 初步分析将以2.0厘米的间隔绘制。

Based on currently available data, we believe that airway responsiveness is an independent, quantitative trait of the asthmatic lesion that is under genetic control. It is known that the variability in airway responsiveness within a given strain of inbred mice is small while the variability in airway responsiveness among strains is quite substantial. The presence of strain-related phenotypic variability in airway responsiveness in mice suggests the possibility that the genetic loci specifically responsible for airway responsiveness can be identified through appropriate genetic studies. The availability of extended chromosome maps for the mouse, computer programs for tracking multiple genetic loci which contribute in an quantitative way to a given phenotypic trait, and the ability to perform molecular genetic mapping with high resolution on small quantities of blood, now make it possible to define genetic linkage for quantitative traits. Airway responsiveness to methacholine as well as 5-hydroxytryptamine (5- HT) as indicated by the infused dose required to decrease pulmonary conductance (GL) by 50% will be determined in A/J, C57BL/6, C57BL/6xA/J F1 and recombinant inbred (RI) mice derived from these progenitor strains. The responsiveness data will be subject to analysis to determine if one or more than one genetic locus influences airway responsiveness to each mediator and whether there exists common loci that influence airway responsiveness to both mediators. Once the mode of inheritance and its mono- or polygenic nature is established mice derived from appropriate crosses will be genotyped using polymorphic markers that span the genome at 10 cM intervals. The data will be subject to linkage analysis using a strategy that allows consideration of either single or multiple genes to influence the phenotypical expression of airway responsiveness as a quantitative trait. In particular, linkage will be sought between the inheritance pattern of polymorphic markers and the airway responsiveness phenotype. Candidate loci, identified through primary analysis will be mapped at 2.0 cM intervals.