Activin type II receptor antagonists: mechanism of action and biological applications

激活素是生长和分化因子的TGF-家族的成员。在小鼠中的过度表达导致肌肉和肝脏消耗、伤口愈合过程中的瘢痕形成、生殖系统紊乱和各种内分泌紊乱。激活素的生物活性通过其与称为I型和II型的两种受体的串联结合来促进。该研究者先前的研究表明，激活素蛋白结构的选择性修饰可以产生与II型受体结合但不能促进与I型受体结合的激活素形式（在这种情况下称为激活素-M108 A）。这导致了激活素-M108 A可能竞争天然激活素与II型受体的结合，从而阻止激活素募集I型受体，结果激活素的生物活性被抑制的假设。建议通过产生足够量的激活素M108 A并在几种肝损伤、肌肉变性和卵巢及睾丸疾病的小鼠模型中测试其抑制作用来测试这一假设。如果激活素-M108 A或激活素的相关修饰形式降低与这些鼠疾病相关的发病率和死亡率，那么我们设想这些激活素II型受体拮抗剂也将有益于治疗相关的人类病症。

Activin is a member of the TGF- family of growth and differentiation factors. Over-expression in mice leads to muscle and liver wasting, scarring during wound healing, disturbances to the reproductive system and various endocrine disorders. Activin's biological activity is promoted by its binding in series to two receptors termed Type I and II. Previous studies by this investigator have shown that selective modification of activin's protein structure can result in activin forms (in this instance called activin-M108A) which bind to Type II receptors but fail to promote binding to the Type I receptor. This has led to the hypothesis that activin-M108A may compete for native activin binding to Type II receptors and thus prevent activin's recruitment of the Type I receptor with the consequence that activin's biological activity is inhibited. It is proposed to test this hypothesis by producing sufficient amounts of activin-M108A and testing its inhibitory effects in several mouse models of liver damage, muscular degeneration and ovarian and testicular disease. If activin-M108A, or related modified forms of activin, decrease the morbidity and mortality associated with these murine diseases, then we envisage that these activin type II receptor antagonists will also be beneficial for the treatment of related human conditions.