MODIFIER GENES FOR CYSTIC FIBROSIS

影响呼吸道离子转运调控的基因 上皮细胞可能编码CF药物治疗的潜在靶点。 使用鼻电位差（PD）作为 电解质转运，我们在小鼠中发现， Agglutinase基因座影响由氯化物引起的PD的变化 梯度离心在来源于129/Sv和C57/BL/6品系的小鼠群体中， 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， 减少CFTR mRNA量的突变不响应于 而CFTR无效突变的纯合子小鼠不具有氯化物梯度， 对氯化物梯度以及腺苷酸环化酶激活的反应， 刺激CFTR通道活性。此外，PD的变化引起 氯离子梯度对DPC敏感。这些数据一起 表明这两种反应都依赖于CFTR，但离子转运 每一个涉及的机制都是不同的。这两种反应都降低了，或者 在CF中不存在，表明这些现象与CF相关 病理生理学所描述的性状似乎不是单基因的 事件，所以我们提出（目的1），以确定基因参与这些 通过定位和克隆与agglutinase基因座连锁的基因， 以及识别与分布在小鼠体内的标记物相关的基因 基因组在目标2中，我们希望更好地理解 CFTR和其他通道的反应涉及鼻腔。也作为 作为这一目标的一部分，我们将研究先天性心脏病患者的PD特征， 双侧输精管缺失，因为其中一些明显 类似于小鼠的氯化物梯度反应。 这些基因可能是治疗靶点的证据将是 如果他们能改变疾病的某些方面，CF小鼠不 因此，目标3将利用一种模式， 气道感染，以确定具有不同鼻PD特征的小鼠 对感染的反应不同，无论是在炎症方面， 生存一旦各种小鼠基因被定位，目标4提出， 确定人类同源物的位置，并确定 人类基因与不同的临床特征相关，例如年龄， 殖民化，FEV/1下降率等。总之，这些目标应该 使我们能够更好地了解电解质运输过程， 希望能找到控制CF发病机制方法。

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.