新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » BIOON报道 » PLoS ONE:恢复关键蛋白CFTR功能有望治疗囊性纤维化

PLoS ONE:恢复关键蛋白CFTR功能有望治疗囊性纤维化

来源:生物谷 2014-02-13 22:29

2014年2月13日讯 /生物谷BIOON/--由斯坦福大学研究人员设计的一个新的测试,有助于更容易开发囊性纤维化的治疗方法。该采取汗液样本的测试表明,少量的特定蛋白质对于改善囊性纤维化症状是必要的。

斯坦福大学心理学和生物学教授Jeffrey Wine和同事在医学斯坦福学校开发出新的测试,使用新的测验方法,测定服用囊性纤维化药物患者中特定蛋白水平。这项研究目前也已发表在PLoS ONE上。

囊性纤维化是一种隐性遗传性疾病,关键蛋白--囊性纤维化跨膜电导调节因子或CFTR被破坏,CFTR负责输送流体和矿物质在细胞中的进出。

Wine的32岁女儿尼娜,患有囊性纤维化。她很幸运,到目前为止,能足够健康跑马拉松,攻读全球健康硕士学位,Wine说,但她依靠药物鸡尾酒来维护她的健康。

当出现治疗囊性纤维化,医生通常只缓解症状。极少数药物能针对潜在的根本问题:即患者的CFTR被破坏,损坏或丢失。

CFTR的缺陷差别很大:或整个蛋白质可能会缺失,或者它可能只是有一些缺陷。当前的开发出的测试,测量汗液中氯化物的量,也不能精确地确定多少正常CFTR的存在。Wine的工作表明,即使是健康的人也具有不同的CFTR水平,并且仅需要少量的CFTR来保持健康。

因此,开发药物有一个较低的目标要求是:只需要恢复CFTR功能的10%,以缓解症状。此外,患者可以用药物补充他们个人的CFTR水平,以缓解症状。这是特别重要的,因为具有相同遗传缺陷的人可以有不同数量的CFTR。

研究人员检查了八名囊性纤维化患者的CFTR水平。六位患者服用ivacaftor,ivacaftor目前可用于治疗某些类型的囊性纤维化。Ivacaftor如预期升高CFTR水平,但它也增加了一类囊性纤维化的CFTR水平。

接下来,Wine说,他计划研究健康个体中CFTR的差异。他希望最终确定缓解症状所需的CFTR精确数量。(生物谷Bioon.com)

 

In Vivo Readout of CFTR Function: Ratiometric Measurement of CFTR-Dependent Secretion by Individual, Identifiable Human Sweat Glands

Jeffrey J. Wine,et al.

To assess CFTR function in vivo, we developed a bioassay that monitors and compares CFTR-dependent and CFTR-independent sweat secretion in parallel for multiple (~50) individual, identified glands in each subject. Sweating was stimulated by intradermally injected agonists and quantified by optically measuring spherical sweat bubbles in an oil-layer that contained dispersed, water soluble dye particles that partitioned into the sweat bubbles, making them highly visible. CFTR-independent secretion (M-sweat) was stimulated with methacholine, which binds to muscarinic receptors and elevates cytosolic calcium. CFTR-dependent secretion (C-sweat) was stimulated with a β-adrenergic cocktail that elevates cytosolic cAMP while blocking muscarinic receptors. A C-sweat/M-sweat ratio was determined on a gland-by-gland basis to compensate for differences unrelated to CFTR function, such as gland size. The average ratio provides an approximately linear readout of CFTR function: the heterozygote ratio is ~0.5 the control ratio and for CF subjects the ratio is zero. During assay development, we measured C/M ratios in 6 healthy controls, 4 CF heterozygotes, 18 CF subjects and 4 subjects with ‘CFTR-related’ conditions. The assay discriminated all groups clearly. It also revealed consistent differences in the C/M ratio among subjects within groups. We hypothesize that these differences reflect, at least in part, levels of CFTR expression, which are known to vary widely. When C-sweat rates become very low the C/M ratio also tended to decrease; we hypothesize that this nonlinearity reflects ductal fluid absorption. We also discovered that M-sweating potentiates the subsequent C-sweat response. We then used potentiation as a surrogate for drugs that can increase CFTR-dependent secretion. This bioassay provides an additional method for assessing CFTR function in vivo, and is well suited for within-subject tests of systemic, CFTR-directed therapeutics.

 

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库