MECHANISM OF ACTION OF HALOFUGINONE AS A NOVEL THERAPEUTIC

描述(申请人提供)：使用小分子在体内操纵代谢功能已成为治疗广泛疾病病理的一种重要的新方法。氨基酸饥饿反应(AAR)是一种信号通路，控制多种代谢和细胞保护功能，以响应氨基酸供应的限制。在我们的初步实验中，我们发现常青藤酮是一种小分子，在涉及纤维化和血管生成的各种动物疾病模型中具有疗效，是AAR的有效和特异的激活剂。我们还发现，常青酮通过一种新的机制激活AAR，并且不依赖于AAR信号的最佳介体发挥作用。通过这种新的信号机制，HF调节与疾病病理或发病机制相关的各种先前描述的细胞行为。我们还确定了HF在体外和体内对促炎T细胞分化的一种新的、特异的作用。HF在体内以体外效应预测的方式改变T细胞群。HF可减轻自身免疫小鼠模型中的炎症病理，表明HF作为治疗自身免疫和慢性炎症性疾病的一类新药物具有很强的潜力。这些观察为理解HF和其他具有类似分子靶点的小分子如何在与慢性炎症性疾病相关的病理学治疗中具有新的和意想不到的用途开辟了一系列令人兴奋的新机会。 公共卫生相关性：我们已经确定了一种小分子，在动物模型中，它可以有效地治疗与多种疾病相关的病理组织变化，包括多发性硬化症、硬皮病、肌肉营养不良和糖尿病肾病。我们计划将这种分子的作用机制描述为一种新的疾病治疗方法。

DESCRIPTION (provided by applicant): The use of small molecules to manipulate metabolic function in vivo has emerged as an important new approach to therapy for a wide range of disease pathologies. The amino acid starvation response (AAR) is a signaling pathway that controls a variety metabolic and cytoprotective functions in response to the restriction of amino acid availability. In our preliminary experiments we have found that halofuginone, a small molecule with efficacy in a variety of animal disease models involving fibrosis and angiogenesis, is a potent and specific activator of the AAR. We have also found that halofuginone activates the AAR through a novel mechanism, and acts independently of the best characterized mediator of AAR signaling. Through this novel signaling mechanism, HF regulates a variety of previously described cell behaviors associated with disease pathology or pathogenesis. We have also identified a novel, specific effect of HF on the differentiation in vitro and in vivo pro-inflammatory T-cells. HF alters T-cell populations in vivo in a way predicted by its effects in vitro. HF reduces inflammatory pathology in a mouse model of autoimmunity, indicating that HF has strong potential as a new class of therapeutic for autoimmune and chronic inflammatory disease. These observations open an exciting new set of opportunities for understanding how HF, and other small molecules with similar molecular targets, may have new and unexpected uses for the treatment of pathology associated with chronic inflammatory disease. PUBLIC HEALTH RELEVANCE: We have identified a small molecule that in animal models is effective for the treatment of pathological tissue changes associated with a wide range of diseases, including multiple sclerosis, scleroderma, muscular dystrophy, and diabetic nephropathy. We plan to characterize the mechanism of action of this molecule as a new class of disease therapeutic.