MODIFIER GENES FOR CYSTIC FIBROSIS

影响离子跨呼吸道运输调节的基因 上皮细胞可能编码了CF药物治疗的潜在靶点。 用鼻电位差(Pd)作为变化的指标 电解质转运，我们在小鼠身上发现了一种与 刺鼠基因影响氯化物引起的帕金森氏反应的变化 渐变。在来自129/Sv和C57/BL/6菌株的小鼠群体中， 有两种明显的表型：对氯化物有反应的表型 梯度和那些没有梯度的。我们还发现携带 降低CFTRmRNA数量的突变不会对 氯离子梯度，而CFTR零突变纯合子小鼠不会 对氯离子梯度和腺苷环化酶激活的反应，a 对CFTR通道活性的刺激。此外，PD的变化唤起了 受氯化物梯度影响，对DPC很敏感。总而言之，这些数据 表明这两种反应都依赖于CFTR，但离子传输 每一种方法涉及的机制都不同。两个响应都减少或 在CF中不存在，这表明这些现象与CF相关 病理生理学。所描述的特征似乎不是单基因。 事件，所以我们建议(目标1)识别与这些事件有关的基因 通过定位和克隆与刺鼠基因连锁的基因进行处理，如 以及识别与散布在老鼠身上的标记相关联的基因 基因组。在目标2中，我们希望更好地了解 CFTR等渠道的反应参与了鼻腔的反应。也可以作为 作为这一目标的一部分，我们将检查患有先天性心脏病的男性的帕金森病特征。 双侧输精管缺如，因为其中一些输精管明显 在氯离子梯度反应方面，与小鼠相似。 相关基因可能成为治疗靶点的证据将是 如果他们能改变疾病的某些方面，就会有所收获。Cf小鼠不会 自发性呼吸道疾病，因此目标3将利用一种模式 呼吸道感染以确定具有不同鼻部帕金森病特征的小鼠 对感染的反应不同，无论是在炎症方面还是在 生死存亡。一旦绘制了各种小鼠基因的图谱，Aim 4建议 确定人类同源基因的位置并确定是否存在等位基因 人类基因与不同的临床特征有关，如年龄 殖民、FEV/1下降速度等。总的来说，这些目标应该 使我们能够更好地了解电解质的运输过程，并且， 希望能找到控制CF发病机制的方法。

Genes influencing the regulation of ion transport across respiratory epithelium may encode potential targets for pharmacologic treatment of CF. Using the nasal potential difference (PD) as an indicator of changes in electrolyte transport, we have found in mice that a gene associated with the agouti locus influences the change in PD elicited by a chloride gradient. In a colony of mice derived from strains of 129/Sv and C57/BL/6, there are two apparent phenotypes: those that respond to a chloride gradient and those that don't. We have also found that mice carrying a mutation which reduces the amount of CFTR mRNA do not respond to a chloride gradient whereas mice homozygous for CFTR null mutations do not respond to chloride gradients as well as adenylate cyclase activation, a stimulation for CFTR channel activity. Furthermore, the change in PD evoke by the chloride gradient is sensitive to DPC. Together, these data indicate both responses are CFTR-dependent, but the ion transport mechanisms involved in each are different. Both responses are reduced or absent in CF, suggesting these are phenomena relevant to CF pathophysiology. The traits described do not appear to be single gene events, so we propose (Aim 1) to identify genes involved in these processed by mapping and cloning the gene linked to the agouti locus, as well as identify genes linked to markers dispersed throughout the mouse genome. In Aim 2, we hope to better understand the relationship between CFTR and other channels in the response of the nasal involved. Also as part of this aim, we will examine the PD profiles of men with congenital bilateral absence of the vas deferens, as some of these are strikingly similarly to the mice with regards to the chloride gradient response. Evidence that the genes involve could be therapeutic targets would be gained if they could modify some aspect of disease. CF mice do not spontaneously develop airway disease, so Aim 3 will utilize a mode of airway infection to determine if mice with different nasal PD profiles respond different to infection, either in terms of inflammation or survival. Once the various murine genes are mapped, Aim 4 proposes to identify the location of the human homologues and determine if alleles of the human genes associate with different clinical traits, such as age of colonization, rate of decline in FEV/1, etc. In all, these aims should allow us to better understand electrolyte transport processes, and, hopefully, identify ways to control CF pathogenesis.