Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum
Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum
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DOI：
10.1126/science.287.5454.826
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发表时间：
2000-02-04
期刊：
影响因子：
56.9
通讯作者：
Clackson, T
中科院分区：
文献类型：
--
作者：
Rivera, VM;Wang, XR;Clackson, T
开发了一种直接药物控制蛋白分泌的系统，以允许快速和脉冲递送治疗蛋白。一种蛋白质经过工程改造，使其在内质网中聚集成聚集体。然后用一种合成的小分子药物刺激分泌，这种药物可以诱导蛋白质分解。体外和体内均能快速、短暂地分泌生长激素和胰岛素。调节胰岛素分泌的脉冲导致高血糖小鼠模型中血清葡萄糖浓度的短暂纠正。这种方法可能使基因治疗成为一种可行的多肽递送方法，需要快速和调节递送。
A system for direct pharmacologic control of protein secretion was developed to allow rapid and pulsatile delivery of therapeutic proteins. A protein was engineered so that it accumulated as aggregates in the endoplasmic reticulum. Secretion was then stimulated by a synthetic small-molecule drug that induces protein disaggregation. Rapid and transient secretion of growth hormone and insulin was achieved in vitro and in vivo. A regulated pulse of insulin secretion resulted in a transient correction of serum glucose concentrations in a mouse model of hyperglycemia. This approach may make gene therapy a viable method for delivery of polypeptides that require rapid and regulated delivery.